{"gene":"INCENP","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1987,"finding":"INCENP (inner centromere protein) was identified as a chromosomal protein that localizes to the inner centromere region between sister chromatids through metaphase, then dissociates from chromosomes at anaphase and transfers to the central spindle and forming contractile ring, ultimately concentrating at the midbody before being discarded at cytokinesis completion.","method":"Monoclonal antibody immunofluorescence microscopy of mitotic cells; biochemical fractionation showing INCENP is tightly associated with the chromosome scaffold fraction","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — original discovery paper using specific antibody and cell fractionation, foundational observation replicated extensively across multiple subsequent studies","pmids":["3316246"],"is_preprint":false},{"year":1998,"finding":"INCENP has a modular organization: an autonomous N-terminal centromere- and midbody-targeting module within the first 68 amino acids containing two conserved motifs (a 13-aa motif required for centromere targeting/spindle transfer, and an 11-aa motif required for spindle transfer after centromere targeting). INCENP also physically interacts with heterochromatin protein HP1(Hsalpha) via yeast two-hybrid and in vitro binding assays, though this interaction does not appear to mediate centromere targeting.","method":"Deletion mutagenesis with GFP-tagged truncation constructs; yeast two-hybrid screen; in vitro binding assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple deletion constructs with defined phenotypes, yeast two-hybrid confirmed by in vitro binding, replicated in subsequent domain-mapping studies","pmids":["9864353"],"is_preprint":false},{"year":1998,"finding":"An INCENP truncation mutant (INCENP1-405) that targets to centromeres but lacks the microtubule association region acts as a dominant-negative, displacing endogenous INCENP from centromeres and impairing both prometaphase chromosome alignment and cytokinesis completion, establishing a functional link between centromere association and cytoskeletal events.","method":"Expression of truncation mutants in cultured cells; immunofluorescence; dominant-negative phenotype analysis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative approach with clear phenotypic readout, single lab with two orthogonal methods (localization + functional assay)","pmids":["9490714"],"is_preprint":false},{"year":2000,"finding":"INCENP directly binds Aurora B kinase (AIRK2/XAIRK2) in vitro and in vivo; INCENP is required to target Aurora B correctly to centromeres and the central spindle. The conserved C-terminal IN-box domain of INCENP mediates this interaction, and this interaction is evolutionarily conserved (Sli15 is the yeast INCENP ortholog based on the IN-box motif).","method":"Co-immunoprecipitation from Xenopus egg extracts; in vitro binding; co-localization by immunofluorescence; yeast genetic analysis","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, in vitro binding, localization studies, replicated across multiple species and labs","pmids":["10996078"],"is_preprint":false},{"year":2000,"finding":"In C. elegans, ICP-1 (INCENP ortholog) and AIR-2 (Aurora B ortholog) form a complex essential for chromosome segregation and cytokinesis; ICP-1 promotes stable localization of ZEN-4 (centralspindlin kinesin) to the central spindle.","method":"RNA-mediated interference (RNAi) in C. elegans embryos; in vitro binding; co-immunoprecipitation of mammalian orthologs","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi loss-of-function with specific phenotypic readout, in vitro binding, co-IP in mammalian cells, replicated across labs","pmids":["11050385"],"is_preprint":false},{"year":2001,"finding":"In Drosophila, INCENP and Aurora B bind each other in vitro; INCENP is required for Aurora B to localize properly and function as a histone H3 kinase; Aurora B is required for INCENP accumulation at centromeres and transfer to the spindle at anaphase. RNAi of either protein impairs chromosome alignment, causes sister kinetochore disjunction defects, and leads to cytokinesis failure.","method":"dsRNA-mediated RNAi in Drosophila cultured cells; in vitro binding; immunofluorescence; biochemical fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi with specific phenotypes, in vitro binding, cross-validated with Aurora B requirement, replicated in multiple organisms","pmids":["11352945"],"is_preprint":false},{"year":2001,"finding":"INCENP localization at the inactive centromere (of stable dicentric chromosomes) correlates strictly with the state of sister chromatid cohesion: loss of cohesion is accompanied by loss of INCENP from the inactive centromere, suggesting INCENP association with centromeres depends on sister chromatid cohesion and not on an active kinetochore.","method":"Immunofluorescence on stable dicentric chromosomes with inactive centromeres in human cells","journal":"Chromosoma","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, single method (immunofluorescence), but uses a unique experimental system (stable dicentric chromosomes) providing specific mechanistic insight","pmids":["11734997"],"is_preprint":false},{"year":2001,"finding":"Survivin directly binds both Aurora B and INCENP by yeast two-hybrid and in vitro pull-down assays; the Survivin-Aurora B interaction resists 3M NaCl. Disruption of INCENP localization in vivo prevents Survivin from concentrating at centromeres or transferring to the anaphase spindle midzone, demonstrating INCENP-dependent targeting of Survivin.","method":"Yeast two-hybrid; in vitro pull-down; live-cell Survivin-GFP imaging; co-immunoprecipitation","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro pull-down, in vivo functional consequence of INCENP disruption on Survivin localization, multiple orthogonal methods","pmids":["11516652"],"is_preprint":false},{"year":2001,"finding":"INCENP binds directly to beta-tubulin (via residues 48–85) and to polymerized microtubules in vitro, and bundles microtubules when expressed in interphase cytoplasm. Targeting of INCENP to the cleavage plane requires dynamic microtubules but not F-actin.","method":"Yeast two-hybrid; in vitro binding to purified tubulin/microtubules; treatment with microtubule and actin-depolymerizing drugs; immunofluorescence","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified tubulin, confirmed by yeast two-hybrid and drug perturbation, multiple orthogonal approaches","pmids":["11139336"],"is_preprint":false},{"year":2002,"finding":"In yeast (Ipl1/Aurora B – Sli15/INCENP), the complex promotes chromosome bi-orientation by promoting turnover of kinetochore-spindle pole body connections. In ipl1 mutants, kinetochores remain attached to old SPBs rather than detaching and reattaching to achieve bi-orientation.","method":"Yeast genetics; time-lapse microscopy; cell cycle analysis with unreplicated chromosomes; spindle pole body duplication assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — elegant genetic experiment in yeast with specific mechanistic readout, widely replicated, foundational for Aurora B bi-orientation model","pmids":["11853667"],"is_preprint":false},{"year":2002,"finding":"C. elegans Aurora B (AIR-2) directly phosphorylates INCENP (ICP-1) at two adjacent serines in the C-terminus; this phosphorylation stimulates AIR-2 kinase activity in a positive feedback loop. Mutation of both serines abolishes the potentiation of AIR-2 activity by ICP-1.","method":"In vitro kinase assay with recombinant proteins; site-directed mutagenesis of phosphorylation sites; kinase activity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation with mutagenesis validation, mechanism independently confirmed in human/Xenopus systems","pmids":["12048181"],"is_preprint":false},{"year":2002,"finding":"Xenopus Survivin, Aurora B, and INCENP form a ternary complex throughout the cell cycle; Survivin and Aurora B bind different domains on INCENP. Survivin binding stimulates Aurora B kinase activity >10-fold (with cell-cycle-dependent phosphorylation required for full activation). The hydrodynamic properties of the complex are cell cycle regulated.","method":"Co-immunoprecipitation from Xenopus embryo extracts; kinase activity assays; phosphatase treatment; gel filtration (hydrodynamic analysis)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, biochemical fractionation, co-IP from native extracts, multiple orthogonal methods in one study","pmids":["12221116"],"is_preprint":false},{"year":2002,"finding":"In Xenopus, the INCENP-Aurora B kinase complex phosphorylates histone H3 and regulates ISWI chromatin remodeling complex association with chromatin; ISWI depletion does not affect chromosome condensation, challenging the model that H3 phosphorylation is required for condensation.","method":"Immunodepletion from Xenopus egg extracts; chromatin assembly assays; histone H3 phosphorylation assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunodepletion in cell-free Xenopus extracts with biochemical readout, single lab but multiple assays","pmids":["11809820"],"is_preprint":false},{"year":2003,"finding":"Human Aurora B kinase activity is stimulated by INCENP; the C-terminal region (IN-box) of INCENP is sufficient for activation. Aurora B phosphorylates INCENP at Thr893, Ser894, and Ser895 (identified by mass spectrometry); a non-phosphorylatable mutant (TSS893-895AAA) is a poor activator of Aurora B, demonstrating INCENP phosphorylation drives a positive feedback loop for Aurora B activation.","method":"Recombinant protein kinase assays; RNA interference (RNAi) depletion; mass spectrometry phosphosite identification; site-directed mutagenesis; immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis, MS-identified phosphosites, multiple orthogonal methods, replicated across species","pmids":["12925766"],"is_preprint":false},{"year":2003,"finding":"Yeast Cdc14 phosphatase dephosphorylates Sli15 (yeast INCENP), directing the Ipl1 (Aurora B)-Sli15 complex from kinetochores to spindles at anaphase. Separase activates Cdc14, which is then sufficient to trigger Sli15 dephosphorylation and relocalization, linking chromosome segregation (cohesin cleavage) to spindle midzone assembly.","method":"Yeast genetics; in vitro phosphatase assays; live-cell imaging; conditional mutant analysis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro dephosphorylation assay, genetic epistasis, sufficiency experiment with separase activation, replicated in subsequent studies","pmids":["14605209"],"is_preprint":false},{"year":2004,"finding":"Aurora C directly binds INCENP in vivo and in vitro; INCENP binding activates Aurora C kinase activity. Aurora C co-expressed with INCENP phosphorylates endogenous histone H3 in mammalian cells. Aurora C forms a complex with Aurora B and INCENP as a chromosomal passenger protein.","method":"Co-immunoprecipitation; in vitro kinase assays; transfection and immunofluorescence in mammalian cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding and kinase activation confirmed, co-IP in vivo, multiple methods in one study","pmids":["15316025"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of Aurora B kinase in complex with the IN-box segment of INCENP (and inhibitor Hesperadin) reveals that INCENP forms a crown around the small lobe of Aurora B, allosterically inducing the active conformation of the T loop. Phosphorylation of two serines in the INCENP C-terminus generates the fully active kinase from an intermediate state where the Aurora B C-terminal segment stabilizes an open conformation of the catalytic cleft.","method":"X-ray crystallography; structure-function analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at atomic resolution with mechanistic interpretation, foundational structural paper for Aurora B activation mechanism","pmids":["15866179"],"is_preprint":false},{"year":2005,"finding":"Cdk1 phosphorylates INCENP at Thr59 and Thr388, regulating Aurora B localization and activity from prophase to metaphase. Phosphorylation at Thr388 is specifically required for recruitment of Plk1 to the kinetochore; T388A mutant delays metaphase-to-anaphase transition. INCENP thus mediates complex formation between Plk1 and Aurora B on kinetochores.","method":"In vitro kinase assays; siRNA rescue with INCENP phosphorylation mutants; immunofluorescence; co-immunoprecipitation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation identified sites, siRNA rescue with point mutants established functional consequence, co-IP demonstrated complex formation","pmids":["16378098"],"is_preprint":false},{"year":2005,"finding":"INCENP is required for recruiting MKLP1 (mitotic kinesin-like protein 1) to the spindle midzone/midbody; RNAi depletion of INCENP causes abnormal spindle midzone/midbody formation and binucleation. MKLP1 depletion abrogates midbody formation but not midzone assembly or chromosome segregation.","method":"RNA interference; immunofluorescence; 3D reconstruction live-cell imaging","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with specific phenotypic readout, epistasis between INCENP and MKLP1, single lab with two orthogonal imaging methods","pmids":["15796717"],"is_preprint":false},{"year":2006,"finding":"A ternary subcomplex of Survivin, Borealin, and the N-terminal 58 amino acids of INCENP is essential and sufficient for centromere targeting of the chromosomal passenger complex; Aurora B kinase is not required for centromere localization of this subcomplex. CPC centromere targeting does not require CENP-A or hMis12.","method":"In vitro binding assays; siRNA rescue with structure-based mutants; co-immunoprecipitation; immunofluorescence; stable cell line generation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — sufficiency established by minimal subcomplex reconstitution, siRNA rescue with specific mutants, independent confirmation by crystal structure in same year","pmids":["16571674"],"is_preprint":false},{"year":2006,"finding":"INCENP and Aurora B promote meiotic sister chromatid cohesion through localization of the cohesion protector protein MEI-S332; INCENP binds MEI-S332 directly, and MEI-S332 is an in vitro substrate of Aurora B kinase. A MEI-S332 mutant poorly phosphorylated by Aurora B is defective in centromere localization.","method":"Drosophila incenp mutant analysis; in vitro kinase assays; co-immunoprecipitation/binding assays; immunofluorescence","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, genetic loss-of-function, direct binding demonstrated, multiple orthogonal methods","pmids":["16824953"],"is_preprint":false},{"year":2007,"finding":"Crystal structure at 1.4 Å resolution of the Survivin-Borealin-INCENP regulatory core of the CPC reveals that Borealin and INCENP associate with the helical domain of Survivin to form a tight three-helical bundle. siRNA rescue with structure-based mutants shows that intertwined structural interactions of core components create functional interdependence for central spindle and midbody localization.","method":"X-ray crystallography (1.4 Å); siRNA rescue with structure-based mutants; analytical ultracentrifugation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure validated by siRNA rescue and mutagenesis, rigorous structural and functional study","pmids":["17956729"],"is_preprint":false},{"year":2007,"finding":"In Dictyostelium, INCENP localization to the cleavage furrow cortex requires the kinesin-6-related protein Kif12 and involves direct binding of the INCENP N-terminus to the actin cytoskeleton. Kif12 is required for INCENP transfer from the central spindle to the furrow cortex, but not for redistribution from centromeres to the central spindle.","method":"Kif12 knockout analysis; domain truncation mutants; in vitro actin binding assays; immunofluorescence","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro actin binding confirmed, genetic knockout with specific phenotype, domain mapping, single lab","pmids":["17567958"],"is_preprint":false},{"year":2009,"finding":"INCENP C-terminus interactions with Aurora B modulate the level of kinase activity in vivo, which in turn regulates CPC localization and distinct mitotic functions. Low kinase activity is sufficient for spindle checkpoint response when microtubules are absent, intermediate activity supports robust taxol checkpoint response, but CPC transfer from chromosomes to anaphase spindle midzone requires significantly higher activity levels.","method":"INCENP conditional depletion/rescue with activity mutants; kinase activity measurements; live-cell imaging; spindle checkpoint assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — graded activity mutants dissect distinct CPC functions, multiple phenotypic readouts, establishes activity threshold model","pmids":["19951914"],"is_preprint":false},{"year":2009,"finding":"INCENP plays a catalytic role in Aurora B (AurB) autophosphorylation at Thr232 (activation loop); substoichiometric INCENP concentrations are sufficient for AurB autophosphorylation. The AurB/INCENP-catalysed phosphorylation of peptide substrate proceeds through a rapid equilibrium random Bi Bi kinetic mechanism.","method":"In vitro kinase assays with varying INCENP concentrations; kinetics analysis; mass spectrometry","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro kinase assay defining kinetic mechanism, substoichiometric effect established, rigorous biochemistry","pmids":["18767990"],"is_preprint":false},{"year":2010,"finding":"Cdc14 phosphatase dephosphorylates Sli15 (INCENP) at anaphase onset, relocating the complex from centromeres to the central spindle and preventing re-engagement of the mitotic checkpoint after cohesin cleavage (which releases tension). This establishes an evolutionarily conserved mechanism coupling separase/Cdc14 activation to mitotic checkpoint silencing.","method":"Budding yeast genetics; phosphatase mutant analysis; live-cell imaging; spindle assembly checkpoint assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in yeast, checkpoint functional assay, mechanistically extends prior Cdc14/Sli15 findings","pmids":["20619650"],"is_preprint":false},{"year":2011,"finding":"Ipl1 (Aurora B)-dependent phosphorylation of Sli15 (INCENP) prevents CPC binding to the preanaphase spindle and central spindle until late anaphase; decreased Ipl1-dependent Sli15 phosphorylation drives direct CPC binding to microtubules, influencing microtubule dynamics. Cdk1 and Ipl1/Aurora cooperatively modulate microtubule dynamics through Sli15 phosphorylation.","method":"Yeast genetics; phosphomutant analysis; microtubule dynamics measurements (live imaging); in vitro CPC-microtubule binding assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro binding assay combined with genetic phosphomutants and live-cell dynamics measurements, multiple orthogonal methods","pmids":["21727193"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of human Aurora B kinase domain in complex with human INCENP C-terminal region and inhibitor VX-680 reveals a dimeric arrangement of the Aurora B:INCENP complex confirmed by analytical ultracentrifugation; INCENP binding mode differs significantly from the Xenopus Aurora B:INCENP complex.","method":"X-ray crystallography; analytical ultracentrifugation","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of human complex validated by solution-phase ultracentrifugation, provides structural insight distinct from Xenopus model","pmids":["22920039"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of Xenopus Aurora B-INCENP complex with barasertib inhibitor reveals a crystal-packing contact where the INCENP C-terminus occupies the substrate-binding region of Aurora B, resembling a trans-inhibitory mechanism analogous to protein kinase A inhibition.","method":"X-ray crystallography","journal":"Acta crystallographica. Section F, Structural biology communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure observation only, potential crystal packing artifact not functionally validated","pmids":["24598913"],"is_preprint":false},{"year":2015,"finding":"The central region of chicken INCENP (213 residues) is not a coiled coil but a ~32-nm-long single alpha-helix (SAH) domain; the N-terminal half of this SAH domain directly binds microtubules in vitro. The SAH domain acts as a flexible spacer ('dog leash') allowing Aurora B to reach outer kinetochore substrates while the CPC is anchored at the inner centromere.","method":"Biophysical analysis (CD spectroscopy, analytical ultracentrifugation); in vitro microtubule binding assays; mutagenesis; INCENP-knockout/rescue cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural characterization with multiple biophysical methods, in vitro microtubule binding, functional validation in cells, multiple orthogonal approaches","pmids":["26175154"],"is_preprint":false},{"year":2015,"finding":"PRMT1 arginine methyltransferase methylates INCENP at Arg887 in the Aurora B-binding IN-box region both in vitro and in vivo. R887-methylated INCENP shows lower binding affinity to Aurora B; PRMT1 knockdown or expression of methylation-inactive INCENP attenuates Aurora B activity and causes abnormal chromosome alignment/segregation.","method":"In vitro methylation assays; mass spectrometry; co-immunoprecipitation; kinase activity assays; chromosome segregation analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro methylation with MS confirmation, functional consequence via Aurora B activity and mitotic phenotype, single lab","pmids":["26460953"],"is_preprint":false},{"year":2015,"finding":"The putative coiled-coil domain within INCENP drives midzone localization of Aurora B via a direct electrostatic interaction with microtubules. The CPC multimerizes via INCENP's centromere-targeting (CEN box) domain, which increases microtubule-binding affinity. At anaphase onset, when H2AT120 is dephosphorylated, the microtubule-binding affinity outcompetes centromere affinity, switching CPC from centromere to microtubule localization.","method":"In vitro microtubule binding assays; multimerization assays; cell-based rescue experiments with INCENP mutants; phospho-H2A manipulation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding combined with cell-based mutant rescue, single lab, two orthogonal approaches","pmids":["26166576"],"is_preprint":false},{"year":2016,"finding":"LATS1/2 kinases phosphorylate INCENP at Ser894 (within the TSS motif); this LATS-mediated phosphorylation is necessary and sufficient for Aurora B activation during cytokinesis in cells undergoing multipolar division.","method":"In vitro kinase assays; phosphomutant rescue experiments; Aurora B activity assays in cells; RNA interference","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation demonstrated, functional rescue with mutants, but single lab","pmids":["27512725"],"is_preprint":false},{"year":2016,"finding":"INCENP's actin-binding activity is important for cytokinesis and for midzone microtubule stabilization following furrow ingression; midzone microtubule stabilization depends on actomyosin contraction and Aurora B kinase activity, establishing a feedback between furrow ingression and microtubule dynamics mediated by the CPC.","method":"INCENP actin-binding mutant expression; live-cell imaging; Taxol rescue experiments; Aurora B inhibition","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — actin-binding mutant phenotype with pharmacological rescue, multiple imaging approaches, single lab","pmids":["26898472"],"is_preprint":false},{"year":2017,"finding":"In addition to Survivin and Borealin, the SAH domain of INCENP supports CPC localization to chromatin and mitotic checkpoint function. INCENP SAH domain microtubule binding is negatively regulated by CDK-mediated phosphorylation of flanking segments. Dual recognition of chromatin and microtubules by INCENP is required for robust mitotic arrest.","method":"INCENP mutant rescue in Xenopus egg extracts and mammalian cells; microtubule binding assays; phosphomutant analysis; spindle checkpoint assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple mutants defining SAH domain functions, phosphorylation regulation shown, two model systems, multiple phenotypic readouts","pmids":["28314740"],"is_preprint":false},{"year":2017,"finding":"In budding yeast, spindle association via the INCENP (Sli15) microtubule-binding domain is important for Aurora B (Ipl1) function in chromosome biorientation. Artificial dimerization of a minimal CPC (dimerized last-third of Sli15 + Ipl1) suppresses biorientation defects by promoting spindle association rather than by kinase clustering; a putative helical domain in Sli15 is required even when dimerized.","method":"Engineered minimal CPC with artificial dimerization (budding yeast); in vivo chromosome segregation assays; kinase activity measurements","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — elegant domain engineering approach, genetic rescue, single lab","pmids":["28314741"],"is_preprint":false},{"year":2019,"finding":"The COMA inner kinetochore sub-complex physically interacts with Sli15 (INCENP) and recruits Ipl1-Sli15 (Aurora B-INCENP) to the inner kinetochore independently of Bir1 (survivin). Localization of Ipl1-Sli15 at centromeres or inner kinetochores is required for chromosome bi-orientation, established by engineered recruitment when both Bir1 and COMA are defective.","method":"Yeast genetics; co-immunoprecipitation; engineered kinetochore targeting; chromosome segregation assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Moderate — physical interaction by co-IP, sufficiency established by engineered targeting, genetic epistasis, multiple approaches","pmids":["31006569"],"is_preprint":false},{"year":2019,"finding":"Crystal structures of the fully active AURKC:INCENP complex (with phosphorylated INCENP TSS motif) reveal that TSS motif phosphorylation stabilizes the kinase activation loop of AURKC and alters the substrate-binding surface, explaining the mechanism of synergistic Aurora C/B activation by INCENP phosphorylation. VX-680 inhibitor disrupts phosphorylated INCENP TSS motif binding.","method":"X-ray crystallography; biochemical kinase assays; native MS; thermal stability assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of fully phosphorylated complex with biochemical validation, directly explains mechanism of synergistic activation, multiple structural and biochemical methods","pmids":["31320618"],"is_preprint":false},{"year":2019,"finding":"Phosphomimetic mutations of the INCENP STD-rich motif (phosphorylated by Plk1 in vitro and during mitosis in vivo) induce ectopic furrows and contractile ring formation in a Plk1- and ROCK1-dependent manner, independent of cell cycle and microtubule status. Non-phosphorylatable mutants cause chromosome congression failure and cytokinesis failure.","method":"INCENP conditional-knockout cell line; phosphomimetic and non-phosphorylatable mutant rescue; in vitro Plk1 kinase assay; live-cell imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation by Plk1 identified, rescue experiments in conditional KO cells, Plk1/ROCK1 inhibitor pharmacology, single lab","pmids":["31601613"],"is_preprint":false},{"year":2021,"finding":"An ATM-Chk2-INCENP pathway imposes the abscission checkpoint in response to chromatin bridges. ATM activates Chk2 at late midbodies; Chk2 phosphorylates human INCENP at Ser91, promoting INCENP binding to Mklp2 kinesin, which associates with Cep55 to localize the CPC to the midbody center and delay abscission. Nonphosphorylatable INCENP-Ser91A impairs CPC midbody localization and accelerates abscission; phosphomimetic INCENP-Ser91D rescues abscission delay in Chk2- or ATM-deficient cells.","method":"siRNA knockdown; phosphomimetic/non-phosphorylatable mutant rescue; co-immunoprecipitation; in vivo phosphorylation analysis; live-cell abscission imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-mutant rescue definitively links Chk2 phosphorylation of INCENP-Ser91 to Mklp2 binding and CPC midbody localization, multiple orthogonal methods, functional consequence established","pmids":["33355621"],"is_preprint":false},{"year":2021,"finding":"Phosphorylation of INCENP's intrinsically disordered region (IDR) expands its conformation by increasing net charge, shifting the IDR from globular collapsed states to extended coil conformations. This phosphorylation-regulated length change modulates how Aurora B reaches its kinetochore targets, supporting the 'dog-leash' model.","method":"All-atom and coarse-grain molecular dynamics simulations of INCENP IDR with varying phosphorylation levels","journal":"Journal of molecular biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational simulations only, no experimental validation of the conformational transitions in this study","pmids":["34883116"],"is_preprint":false},{"year":2025,"finding":"CryoEM structure of the CPC (Borealin-Survivin-INCENP) bound to H3Thr3-phosphorylated nucleosomes reveals multipartite interactions: N-terminus of Borealin and Survivin BIR domain act as pivot and flexible tethering points for CPC engagement at the nucleosome acidic patch and DNA entry-exit site. Perturbation of the CPC-nucleosome interaction compromises MNase protection in vitro and dynamic centromere association in cells, revealing a non-catalytic role for CPC in maintaining centromeric chromatin stability.","method":"CryoEM structure determination; atomic force microscopy; MNase protection assays; structure-based mutagenesis with cellular rescue","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with biochemical and cellular validation, multiple methods, but preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"INCENP is the scaffold subunit of the chromosomal passenger complex (CPC; Aurora B/INCENP/Survivin/Borealin) that acts as a platform, activator, and localization determinant for Aurora B kinase: its N-terminal domain forms a three-helix bundle with Survivin and Borealin that targets the CPC to inner centromeres via H3Thr3-phosphorylated nucleosomes, its single-alpha-helix (SAH) central domain directly binds microtubules and acts as a flexible 'dog leash' allowing Aurora B to reach kinetochore substrates, and its C-terminal IN-box directly binds and allosterically activates Aurora B through a positive feedback loop in which Aurora B phosphorylates the INCENP TSS motif to achieve full kinase activation; CPC re-localization from centromeres to the spindle midzone at anaphase is triggered by dephosphorylation of INCENP by Cdc14 phosphatase (activated by separase), and additional regulatory inputs include Cdk1 phosphorylation of INCENP (controlling Plk1 recruitment), Chk2 phosphorylation of INCENP-Ser91 (imposing the abscission checkpoint via Mklp2 binding), and PRMT1 methylation of INCENP-Arg887 (reducing Aurora B binding affinity)."},"narrative":{"mechanistic_narrative":"INCENP is the scaffold subunit of the chromosomal passenger complex (CPC), an evolutionarily conserved machine that coordinates chromosome segregation and cytokinesis by positioning and activating Aurora B kinase across mitosis; it localizes to the inner centromere through metaphase and then transfers to the central spindle, contractile ring, and midbody [PMID:3316246, PMID:10996078]. INCENP is modular: its N-terminal 58 residues form a three-helix bundle with Survivin and Borealin that is essential and sufficient to target the CPC to inner centromeres independently of Aurora B kinase activity [PMID:16571674, PMID:17956729], while its conserved C-terminal IN-box directly binds Aurora B (and the related Aurora C) and is required to localize the kinase to centromeres and the central spindle [PMID:10996078, PMID:15316025]. Binding within this complex allosterically activates Aurora B—the IN-box forms a crown around the kinase small lobe to induce the active T-loop conformation [PMID:15866179]—and Aurora B in turn phosphorylates the INCENP TSS motif (Thr893/Ser894/Ser895), driving a positive-feedback loop that yields the fully active kinase [PMID:12048181, PMID:12925766, PMID:31320618]. The central single-alpha-helix (SAH) domain of INCENP directly binds microtubules and acts as a flexible 'dog-leash' spacer that lets centromere-anchored Aurora B reach outer kinetochore substrates, with this microtubule affinity tuned by CDK phosphorylation of flanking segments [PMID:26175154, PMID:28314740]. Through these activities the CPC promotes chromosome bi-orientation by destabilizing erroneous kinetochore–microtubule attachments [PMID:11853667], protects centromeric cohesion via substrates such as MEI-S332 [PMID:16824953], and directs central-spindle and midbody assembly by recruiting kinesins MKLP1 and Plk1 [PMID:16378098, PMID:15796717]. Relocation from centromeres to the spindle midzone at anaphase is governed by INCENP phosphoregulation: Cdc14 phosphatase, activated by separase, dephosphorylates INCENP/Sli15 to trigger transfer and silence the mitotic checkpoint [PMID:14605209, PMID:20619650], and an electrostatic microtubule-binding switch coupled to H2A dephosphorylation drives the localization change [PMID:26166576]. Additional regulatory inputs include Cdk1 phosphorylation controlling Plk1 recruitment [PMID:16378098], Chk2 phosphorylation of Ser91 imposing the abscission checkpoint through Mklp2 binding [PMID:33355621], and PRMT1 methylation of Arg887 that lowers Aurora B binding affinity [PMID:26460953].","teleology":[{"year":1987,"claim":"Established the existence and dynamic behavior of an inner centromere protein that relocates from chromosomes to the spindle and midbody, defining the phenomenon the gene is named for.","evidence":"Monoclonal antibody immunofluorescence and chromosome scaffold fractionation of mitotic cells","pmids":["3316246"],"confidence":"High","gaps":["No molecular partners or biochemical activity identified","Mechanism of relocation unknown"]},{"year":1998,"claim":"Mapped INCENP into discrete functional modules, localizing centromere/midbody targeting to the N-terminus and revealing that centromere association is functionally coupled to downstream cytoskeletal events.","evidence":"GFP-tagged truncation/deletion mutagenesis, yeast two-hybrid, and dominant-negative expression in cultured cells","pmids":["9864353","9490714"],"confidence":"High","gaps":["HP1 interaction not linked to a function","Microtubule region not yet characterized molecularly"]},{"year":2000,"claim":"Identified INCENP as the direct binding partner and localization determinant for Aurora B kinase via the conserved C-terminal IN-box, defining the core of the CPC across species.","evidence":"Co-IP from Xenopus extracts, in vitro binding, co-localization, and C. elegans RNAi","pmids":["10996078","11050385"],"confidence":"High","gaps":["Activation mechanism of Aurora B by INCENP not established","Structural basis of IN-box binding unknown"]},{"year":2001,"claim":"Showed reciprocal interdependence of INCENP and Aurora B for localization/function and extended the complex to include Survivin and direct microtubule/tubulin binding by INCENP.","evidence":"Drosophila RNAi, yeast two-hybrid, in vitro tubulin/microtubule binding, dicentric chromosome imaging","pmids":["11352945","11516652","11139336","11734997"],"confidence":"High","gaps":["Centromere targeting dependence on cohesion only correlative","Stoichiometry of multi-subunit complex unresolved"]},{"year":2002,"claim":"Defined the positive-feedback activation mechanism—Aurora B phosphorylates the INCENP C-terminus to potentiate its own kinase activity—and established Survivin-INCENP-Aurora B as a stable ternary complex.","evidence":"In vitro kinase assays with phosphosite mutagenesis (C. elegans), co-IP and gel filtration from Xenopus extracts, yeast bi-orientation genetics","pmids":["12048181","12221116","11853667","11809820"],"confidence":"High","gaps":["Atomic basis of allosteric activation not yet known","Quantitative activation thresholds undefined"]},{"year":2003,"claim":"Pinpointed the human INCENP TSS phosphosites (Thr893/Ser894/Ser895) whose phosphorylation drives Aurora B activation, and identified Cdc14-mediated INCENP dephosphorylation as the trigger coupling separase activation to anaphase CPC relocalization.","evidence":"Recombinant kinase assays with MS phosphosite mapping and mutagenesis (human); in vitro phosphatase assays and yeast genetics linking separase/Cdc14 to Sli15","pmids":["12925766","14605209"],"confidence":"High","gaps":["How relocalization silences the checkpoint not yet addressed","Phosphatase regulation of human INCENP not directly shown"]},{"year":2004,"claim":"Extended INCENP's activating partnership to Aurora C, showing INCENP binds and activates a second Aurora kinase as part of a chromosomal passenger complex.","evidence":"Co-IP, in vitro kinase assays, transfection imaging in mammalian cells","pmids":["15316025"],"confidence":"High","gaps":["Physiological context distinguishing Aurora B vs C unclear","Structural basis of AURKC activation not shown"]},{"year":2005,"claim":"Provided the structural and regulatory logic of Aurora B activation by INCENP and defined Cdk1 phosphorylation of INCENP as a node controlling Plk1 recruitment and metaphase-to-anaphase timing.","evidence":"X-ray crystallography of Aurora B:IN-box; in vitro kinase assays and siRNA rescue with INCENP Cdk1-site mutants; co-IP","pmids":["15866179","16378098","15796717"],"confidence":"High","gaps":["How phosphorylation states are spatially read out in vivo not resolved","MKLP1 recruitment mechanism by INCENP not molecularly defined"]},{"year":2006,"claim":"Resolved the minimal centromere-targeting module as a Survivin-Borealin-INCENP(N58) subcomplex and added a meiotic cohesion-protection role through MEI-S332 localization.","evidence":"Minimal subcomplex reconstitution with siRNA rescue; Drosophila incenp mutants with in vitro kinase/binding assays","pmids":["16571674","16824953"],"confidence":"High","gaps":["Centromeric receptor of the subcomplex not identified","How targeting and cohesion protection are temporally coupled unclear"]},{"year":2007,"claim":"Solved the high-resolution structure of the Survivin-Borealin-INCENP regulatory core, explaining the structural interdependence of CPC subunits for localization.","evidence":"1.4 Å X-ray crystallography with siRNA rescue mutants and analytical ultracentrifugation; Dictyostelium actin-binding/Kif12 studies","pmids":["17956729","17567958"],"confidence":"High","gaps":["Connection between core structure and nucleosome engagement not yet known","Actin-binding role conservation in vertebrates not established"]},{"year":2009,"claim":"Established that graded Aurora B activity levels, set by INCENP C-terminal interactions and substoichiometric catalytic activation, partition distinct mitotic functions and define a kinetic activation mechanism.","evidence":"INCENP activity-mutant depletion/rescue with checkpoint assays; quantitative in vitro kinase kinetics","pmids":["19951914","18767990"],"confidence":"High","gaps":["Spatial control of activity thresholds in cells not resolved","Link between activity level and localization switch incomplete"]},{"year":2010,"claim":"Demonstrated that Cdc14-mediated Sli15/INCENP dephosphorylation both relocates the CPC and silences the mitotic checkpoint after cohesin cleavage, establishing a conserved tension-loss bypass mechanism.","evidence":"Budding yeast genetics, phosphatase mutants, and checkpoint assays","pmids":["20619650"],"confidence":"High","gaps":["Direct biochemical targets of dephosphorylation in human cells not mapped"]},{"year":2011,"claim":"Showed that Aurora B-dependent INCENP phosphorylation gates CPC-microtubule binding and that Cdk1 and Aurora cooperatively tune microtubule dynamics through INCENP phosphostate.","evidence":"Yeast phosphomutant genetics, live microtubule dynamics imaging, in vitro CPC-microtubule binding","pmids":["21727193"],"confidence":"High","gaps":["Structural basis of the phospho-controlled microtubule switch not defined"]},{"year":2012,"claim":"Determined the human Aurora B:INCENP complex structure, revealing a dimeric arrangement and species-specific INCENP binding mode distinct from Xenopus.","evidence":"X-ray crystallography with analytical ultracentrifugation","pmids":["22920039"],"confidence":"High","gaps":["Functional significance of dimerization in vivo not established"]},{"year":2014,"claim":"Captured a structural conformation in which the INCENP C-terminus occupies the Aurora B substrate site, hinting at a possible trans-inhibitory state.","evidence":"X-ray crystallography of Xenopus Aurora B-INCENP with inhibitor","pmids":["24598913"],"confidence":"Medium","gaps":["Potential crystal-packing artifact not functionally validated","No cellular evidence for trans-inhibition"]},{"year":2015,"claim":"Defined the central INCENP region as a single-alpha-helix microtubule-binding 'dog-leash' spacer and identified additional regulatory layers (electrostatic localization switch coupled to H2A dephosphorylation; PRMT1 methylation of Arg887 modulating Aurora B affinity).","evidence":"Biophysical SAH characterization with microtubule binding and rescue cell lines; in vitro multimerization/binding with phospho-H2A manipulation; in vitro methylation with MS and mitotic phenotyping","pmids":["26175154","26166576","26460953"],"confidence":"High","gaps":["Quantitative contribution of each affinity in vivo unresolved","PRMT1 methylation findings from single lab"]},{"year":2016,"claim":"Identified LATS1/2 as an alternative INCENP TSS-motif kinase activating Aurora B during multipolar cytokinesis and linked INCENP actin binding to midzone microtubule stabilization feedback.","evidence":"In vitro kinase assays with phosphomutant rescue; actin-binding mutant live imaging with Taxol/Aurora B inhibition","pmids":["27512725","26898472"],"confidence":"Medium","gaps":["LATS1/2 role only shown in multipolar context, single lab","Generality of actin-binding requirement across cell types unclear"]},{"year":2017,"claim":"Showed the SAH domain contributes to chromatin localization and checkpoint function through dual chromatin/microtubule recognition, and that spindle association rather than kinase clustering underlies Aurora B's bi-orientation function.","evidence":"INCENP mutant rescue in Xenopus extracts and mammalian cells; engineered minimal/dimerized CPC in budding yeast with segregation assays","pmids":["28314740","28314741"],"confidence":"High","gaps":["Precise chromatin receptor for the SAH domain not identified"]},{"year":2019,"claim":"Provided the structural mechanism by which TSS-motif phosphorylation fully activates Aurora kinases, identified an alternative kinetochore recruitment route via the COMA complex, and added Plk1 phosphorylation of the INCENP STD-rich motif as a furrow-inducing input.","evidence":"Crystal structures of phosphorylated AURKC:INCENP with biochemical assays; yeast genetics and engineered targeting (COMA); conditional-KO rescue with Plk1 phosphomutants","pmids":["31320618","31006569","31601613"],"confidence":"High","gaps":["Whether COMA recruitment operates in vertebrates not shown","Crosstalk between multiple INCENP phospho-inputs unresolved"]},{"year":2021,"claim":"Established an ATM-Chk2-INCENP-Ser91 axis that imposes the abscission checkpoint by promoting Mklp2-dependent CPC midbody localization, defining a DNA-damage-responsive cytokinesis control through INCENP.","evidence":"siRNA, phosphomimetic/non-phosphorylatable mutant rescue, co-IP, and live abscission imaging","pmids":["33355621"],"confidence":"High","gaps":["How chromatin bridges activate ATM at the midbody not detailed","Conformational basis of the dog-leash extension supported only computationally"]},{"year":2025,"claim":"Revealed a non-catalytic, structural role for the CPC in maintaining centromeric chromatin stability via multipartite engagement of H3Thr3-phosphorylated nucleosomes.","evidence":"CryoEM, AFM, MNase protection, and structure-based mutagenesis with cellular rescue (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","In vivo consequences of chromatin stabilization for segregation fidelity incompletely defined"]},{"year":null,"claim":"How the multiple, often competing INCENP phospho- and methyl-regulatory inputs are integrated in space and time to switch the CPC between its sequential mitotic locations remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model coupling INCENP modifications to localization transitions","Endogenous receptor(s) coordinating SAH-mediated chromatin/microtubule handoff not fully defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,13,16,24,37]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,7,17,19,39]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8,29,31]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[19,21,29]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[8,22,29]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[19,41]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,3,9,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12,41]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[20]}],"complexes":["Chromosomal passenger complex (CPC)"],"partners":["AURKB","AURKC","BIRC5","CDCA8","PLK1","KIF20A","KIF23","HP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NQS7","full_name":"Inner centromere protein","aliases":[],"length_aa":918,"mass_kda":105.4,"function":"Component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Acts as a scaffold regulating CPC localization and activity. The C-terminus associates with AURKB or AURKC, the N-terminus associated with BIRC5/survivin and CDCA8/borealin tethers the CPC to the inner centromere, and the microtubule binding activity within the central SAH domain directs AURKB/C toward substrates near microtubules (PubMed:12925766, PubMed:15316025, PubMed:27332895). The flexibility of the SAH domain is proposed to allow AURKB/C to follow substrates on dynamic microtubules while ensuring CPC docking to static chromatin (By similarity). Activates AURKB and AURKC (PubMed:27332895). Required for localization of CBX5 to mitotic centromeres (PubMed:21346195). Controls the kinetochore localization of BUB1 (PubMed:16760428)","subcellular_location":"Nucleus; Chromosome, centromere; Cytoplasm, cytoskeleton, spindle; Midbody; Chromosome, centromere, kinetochore","url":"https://www.uniprot.org/uniprotkb/Q9NQS7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/INCENP","classification":"Common Essential","n_dependent_lines":1193,"n_total_lines":1208,"dependency_fraction":0.9875827814569537},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"AURKB","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"PRKAA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/INCENP","total_profiled":1310},"omim":[{"mim_id":"614787","title":"POGO TRANSPOSABLE ELEMENT-DERIVED PROTEIN WITH ZNF DOMAIN; POGZ","url":"https://www.omim.org/entry/614787"},{"mim_id":"609977","title":"CELL DIVISION CYCLE-ASSOCIATED PROTEIN 8; CDCA8","url":"https://www.omim.org/entry/609977"},{"mim_id":"609589","title":"MICROTUBULE-ASSOCIATED SCAFFOLD PROTEIN 1; MTUS1","url":"https://www.omim.org/entry/609589"},{"mim_id":"609177","title":"ZW10 INTERACTING KINETOCHORE PROTEIN; ZWINT","url":"https://www.omim.org/entry/609177"},{"mim_id":"604970","title":"AURORA KINASE B; AURKB","url":"https://www.omim.org/entry/604970"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Kinetochore","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Midbody","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":19.8}],"url":"https://www.proteinatlas.org/search/INCENP"},"hgnc":{"alias_symbol":["FLJ31633"],"prev_symbol":[]},"alphafold":{"accession":"Q9NQS7","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQS7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQS7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQS7-F1-predicted_aligned_error_v6.png","plddt_mean":59.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INCENP","jax_strain_url":"https://www.jax.org/strain/search?query=INCENP"},"sequence":{"accession":"Q9NQS7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NQS7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NQS7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQS7"}},"corpus_meta":[{"pmid":"11853667","id":"PMC_11853667","title":"Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole 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transfers to the central spindle and forming contractile ring, ultimately concentrating at the midbody before being discarded at cytokinesis completion.\",\n      \"method\": \"Monoclonal antibody immunofluorescence microscopy of mitotic cells; biochemical fractionation showing INCENP is tightly associated with the chromosome scaffold fraction\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — original discovery paper using specific antibody and cell fractionation, foundational observation replicated extensively across multiple subsequent studies\",\n      \"pmids\": [\"3316246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"INCENP has a modular organization: an autonomous N-terminal centromere- and midbody-targeting module within the first 68 amino acids containing two conserved motifs (a 13-aa motif required for centromere targeting/spindle transfer, and an 11-aa motif required for spindle transfer after centromere targeting). INCENP also physically interacts with heterochromatin protein HP1(Hsalpha) via yeast two-hybrid and in vitro binding assays, though this interaction does not appear to mediate centromere targeting.\",\n      \"method\": \"Deletion mutagenesis with GFP-tagged truncation constructs; yeast two-hybrid screen; in vitro binding assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple deletion constructs with defined phenotypes, yeast two-hybrid confirmed by in vitro binding, replicated in subsequent domain-mapping studies\",\n      \"pmids\": [\"9864353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"An INCENP truncation mutant (INCENP1-405) that targets to centromeres but lacks the microtubule association region acts as a dominant-negative, displacing endogenous INCENP from centromeres and impairing both prometaphase chromosome alignment and cytokinesis completion, establishing a functional link between centromere association and cytoskeletal events.\",\n      \"method\": \"Expression of truncation mutants in cultured cells; immunofluorescence; dominant-negative phenotype analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative approach with clear phenotypic readout, single lab with two orthogonal methods (localization + functional assay)\",\n      \"pmids\": [\"9490714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"INCENP directly binds Aurora B kinase (AIRK2/XAIRK2) in vitro and in vivo; INCENP is required to target Aurora B correctly to centromeres and the central spindle. The conserved C-terminal IN-box domain of INCENP mediates this interaction, and this interaction is evolutionarily conserved (Sli15 is the yeast INCENP ortholog based on the IN-box motif).\",\n      \"method\": \"Co-immunoprecipitation from Xenopus egg extracts; in vitro binding; co-localization by immunofluorescence; yeast genetic analysis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, in vitro binding, localization studies, replicated across multiple species and labs\",\n      \"pmids\": [\"10996078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In C. elegans, ICP-1 (INCENP ortholog) and AIR-2 (Aurora B ortholog) form a complex essential for chromosome segregation and cytokinesis; ICP-1 promotes stable localization of ZEN-4 (centralspindlin kinesin) to the central spindle.\",\n      \"method\": \"RNA-mediated interference (RNAi) in C. elegans embryos; in vitro binding; co-immunoprecipitation of mammalian orthologs\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi loss-of-function with specific phenotypic readout, in vitro binding, co-IP in mammalian cells, replicated across labs\",\n      \"pmids\": [\"11050385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In Drosophila, INCENP and Aurora B bind each other in vitro; INCENP is required for Aurora B to localize properly and function as a histone H3 kinase; Aurora B is required for INCENP accumulation at centromeres and transfer to the spindle at anaphase. RNAi of either protein impairs chromosome alignment, causes sister kinetochore disjunction defects, and leads to cytokinesis failure.\",\n      \"method\": \"dsRNA-mediated RNAi in Drosophila cultured cells; in vitro binding; immunofluorescence; biochemical fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi with specific phenotypes, in vitro binding, cross-validated with Aurora B requirement, replicated in multiple organisms\",\n      \"pmids\": [\"11352945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"INCENP localization at the inactive centromere (of stable dicentric chromosomes) correlates strictly with the state of sister chromatid cohesion: loss of cohesion is accompanied by loss of INCENP from the inactive centromere, suggesting INCENP association with centromeres depends on sister chromatid cohesion and not on an active kinetochore.\",\n      \"method\": \"Immunofluorescence on stable dicentric chromosomes with inactive centromeres in human cells\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, single method (immunofluorescence), but uses a unique experimental system (stable dicentric chromosomes) providing specific mechanistic insight\",\n      \"pmids\": [\"11734997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Survivin directly binds both Aurora B and INCENP by yeast two-hybrid and in vitro pull-down assays; the Survivin-Aurora B interaction resists 3M NaCl. Disruption of INCENP localization in vivo prevents Survivin from concentrating at centromeres or transferring to the anaphase spindle midzone, demonstrating INCENP-dependent targeting of Survivin.\",\n      \"method\": \"Yeast two-hybrid; in vitro pull-down; live-cell Survivin-GFP imaging; co-immunoprecipitation\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro pull-down, in vivo functional consequence of INCENP disruption on Survivin localization, multiple orthogonal methods\",\n      \"pmids\": [\"11516652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"INCENP binds directly to beta-tubulin (via residues 48–85) and to polymerized microtubules in vitro, and bundles microtubules when expressed in interphase cytoplasm. Targeting of INCENP to the cleavage plane requires dynamic microtubules but not F-actin.\",\n      \"method\": \"Yeast two-hybrid; in vitro binding to purified tubulin/microtubules; treatment with microtubule and actin-depolymerizing drugs; immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified tubulin, confirmed by yeast two-hybrid and drug perturbation, multiple orthogonal approaches\",\n      \"pmids\": [\"11139336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In yeast (Ipl1/Aurora B – Sli15/INCENP), the complex promotes chromosome bi-orientation by promoting turnover of kinetochore-spindle pole body connections. In ipl1 mutants, kinetochores remain attached to old SPBs rather than detaching and reattaching to achieve bi-orientation.\",\n      \"method\": \"Yeast genetics; time-lapse microscopy; cell cycle analysis with unreplicated chromosomes; spindle pole body duplication assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — elegant genetic experiment in yeast with specific mechanistic readout, widely replicated, foundational for Aurora B bi-orientation model\",\n      \"pmids\": [\"11853667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"C. elegans Aurora B (AIR-2) directly phosphorylates INCENP (ICP-1) at two adjacent serines in the C-terminus; this phosphorylation stimulates AIR-2 kinase activity in a positive feedback loop. Mutation of both serines abolishes the potentiation of AIR-2 activity by ICP-1.\",\n      \"method\": \"In vitro kinase assay with recombinant proteins; site-directed mutagenesis of phosphorylation sites; kinase activity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation with mutagenesis validation, mechanism independently confirmed in human/Xenopus systems\",\n      \"pmids\": [\"12048181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Xenopus Survivin, Aurora B, and INCENP form a ternary complex throughout the cell cycle; Survivin and Aurora B bind different domains on INCENP. Survivin binding stimulates Aurora B kinase activity >10-fold (with cell-cycle-dependent phosphorylation required for full activation). The hydrodynamic properties of the complex are cell cycle regulated.\",\n      \"method\": \"Co-immunoprecipitation from Xenopus embryo extracts; kinase activity assays; phosphatase treatment; gel filtration (hydrodynamic analysis)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, biochemical fractionation, co-IP from native extracts, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12221116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In Xenopus, the INCENP-Aurora B kinase complex phosphorylates histone H3 and regulates ISWI chromatin remodeling complex association with chromatin; ISWI depletion does not affect chromosome condensation, challenging the model that H3 phosphorylation is required for condensation.\",\n      \"method\": \"Immunodepletion from Xenopus egg extracts; chromatin assembly assays; histone H3 phosphorylation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunodepletion in cell-free Xenopus extracts with biochemical readout, single lab but multiple assays\",\n      \"pmids\": [\"11809820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human Aurora B kinase activity is stimulated by INCENP; the C-terminal region (IN-box) of INCENP is sufficient for activation. Aurora B phosphorylates INCENP at Thr893, Ser894, and Ser895 (identified by mass spectrometry); a non-phosphorylatable mutant (TSS893-895AAA) is a poor activator of Aurora B, demonstrating INCENP phosphorylation drives a positive feedback loop for Aurora B activation.\",\n      \"method\": \"Recombinant protein kinase assays; RNA interference (RNAi) depletion; mass spectrometry phosphosite identification; site-directed mutagenesis; immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis, MS-identified phosphosites, multiple orthogonal methods, replicated across species\",\n      \"pmids\": [\"12925766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yeast Cdc14 phosphatase dephosphorylates Sli15 (yeast INCENP), directing the Ipl1 (Aurora B)-Sli15 complex from kinetochores to spindles at anaphase. Separase activates Cdc14, which is then sufficient to trigger Sli15 dephosphorylation and relocalization, linking chromosome segregation (cohesin cleavage) to spindle midzone assembly.\",\n      \"method\": \"Yeast genetics; in vitro phosphatase assays; live-cell imaging; conditional mutant analysis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro dephosphorylation assay, genetic epistasis, sufficiency experiment with separase activation, replicated in subsequent studies\",\n      \"pmids\": [\"14605209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Aurora C directly binds INCENP in vivo and in vitro; INCENP binding activates Aurora C kinase activity. Aurora C co-expressed with INCENP phosphorylates endogenous histone H3 in mammalian cells. Aurora C forms a complex with Aurora B and INCENP as a chromosomal passenger protein.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assays; transfection and immunofluorescence in mammalian cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding and kinase activation confirmed, co-IP in vivo, multiple methods in one study\",\n      \"pmids\": [\"15316025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of Aurora B kinase in complex with the IN-box segment of INCENP (and inhibitor Hesperadin) reveals that INCENP forms a crown around the small lobe of Aurora B, allosterically inducing the active conformation of the T loop. Phosphorylation of two serines in the INCENP C-terminus generates the fully active kinase from an intermediate state where the Aurora B C-terminal segment stabilizes an open conformation of the catalytic cleft.\",\n      \"method\": \"X-ray crystallography; structure-function analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at atomic resolution with mechanistic interpretation, foundational structural paper for Aurora B activation mechanism\",\n      \"pmids\": [\"15866179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cdk1 phosphorylates INCENP at Thr59 and Thr388, regulating Aurora B localization and activity from prophase to metaphase. Phosphorylation at Thr388 is specifically required for recruitment of Plk1 to the kinetochore; T388A mutant delays metaphase-to-anaphase transition. INCENP thus mediates complex formation between Plk1 and Aurora B on kinetochores.\",\n      \"method\": \"In vitro kinase assays; siRNA rescue with INCENP phosphorylation mutants; immunofluorescence; co-immunoprecipitation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation identified sites, siRNA rescue with point mutants established functional consequence, co-IP demonstrated complex formation\",\n      \"pmids\": [\"16378098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"INCENP is required for recruiting MKLP1 (mitotic kinesin-like protein 1) to the spindle midzone/midbody; RNAi depletion of INCENP causes abnormal spindle midzone/midbody formation and binucleation. MKLP1 depletion abrogates midbody formation but not midzone assembly or chromosome segregation.\",\n      \"method\": \"RNA interference; immunofluorescence; 3D reconstruction live-cell imaging\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with specific phenotypic readout, epistasis between INCENP and MKLP1, single lab with two orthogonal imaging methods\",\n      \"pmids\": [\"15796717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A ternary subcomplex of Survivin, Borealin, and the N-terminal 58 amino acids of INCENP is essential and sufficient for centromere targeting of the chromosomal passenger complex; Aurora B kinase is not required for centromere localization of this subcomplex. CPC centromere targeting does not require CENP-A or hMis12.\",\n      \"method\": \"In vitro binding assays; siRNA rescue with structure-based mutants; co-immunoprecipitation; immunofluorescence; stable cell line generation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — sufficiency established by minimal subcomplex reconstitution, siRNA rescue with specific mutants, independent confirmation by crystal structure in same year\",\n      \"pmids\": [\"16571674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"INCENP and Aurora B promote meiotic sister chromatid cohesion through localization of the cohesion protector protein MEI-S332; INCENP binds MEI-S332 directly, and MEI-S332 is an in vitro substrate of Aurora B kinase. A MEI-S332 mutant poorly phosphorylated by Aurora B is defective in centromere localization.\",\n      \"method\": \"Drosophila incenp mutant analysis; in vitro kinase assays; co-immunoprecipitation/binding assays; immunofluorescence\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, genetic loss-of-function, direct binding demonstrated, multiple orthogonal methods\",\n      \"pmids\": [\"16824953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure at 1.4 Å resolution of the Survivin-Borealin-INCENP regulatory core of the CPC reveals that Borealin and INCENP associate with the helical domain of Survivin to form a tight three-helical bundle. siRNA rescue with structure-based mutants shows that intertwined structural interactions of core components create functional interdependence for central spindle and midbody localization.\",\n      \"method\": \"X-ray crystallography (1.4 Å); siRNA rescue with structure-based mutants; analytical ultracentrifugation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure validated by siRNA rescue and mutagenesis, rigorous structural and functional study\",\n      \"pmids\": [\"17956729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Dictyostelium, INCENP localization to the cleavage furrow cortex requires the kinesin-6-related protein Kif12 and involves direct binding of the INCENP N-terminus to the actin cytoskeleton. Kif12 is required for INCENP transfer from the central spindle to the furrow cortex, but not for redistribution from centromeres to the central spindle.\",\n      \"method\": \"Kif12 knockout analysis; domain truncation mutants; in vitro actin binding assays; immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro actin binding confirmed, genetic knockout with specific phenotype, domain mapping, single lab\",\n      \"pmids\": [\"17567958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"INCENP C-terminus interactions with Aurora B modulate the level of kinase activity in vivo, which in turn regulates CPC localization and distinct mitotic functions. Low kinase activity is sufficient for spindle checkpoint response when microtubules are absent, intermediate activity supports robust taxol checkpoint response, but CPC transfer from chromosomes to anaphase spindle midzone requires significantly higher activity levels.\",\n      \"method\": \"INCENP conditional depletion/rescue with activity mutants; kinase activity measurements; live-cell imaging; spindle checkpoint assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — graded activity mutants dissect distinct CPC functions, multiple phenotypic readouts, establishes activity threshold model\",\n      \"pmids\": [\"19951914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"INCENP plays a catalytic role in Aurora B (AurB) autophosphorylation at Thr232 (activation loop); substoichiometric INCENP concentrations are sufficient for AurB autophosphorylation. The AurB/INCENP-catalysed phosphorylation of peptide substrate proceeds through a rapid equilibrium random Bi Bi kinetic mechanism.\",\n      \"method\": \"In vitro kinase assays with varying INCENP concentrations; kinetics analysis; mass spectrometry\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro kinase assay defining kinetic mechanism, substoichiometric effect established, rigorous biochemistry\",\n      \"pmids\": [\"18767990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cdc14 phosphatase dephosphorylates Sli15 (INCENP) at anaphase onset, relocating the complex from centromeres to the central spindle and preventing re-engagement of the mitotic checkpoint after cohesin cleavage (which releases tension). This establishes an evolutionarily conserved mechanism coupling separase/Cdc14 activation to mitotic checkpoint silencing.\",\n      \"method\": \"Budding yeast genetics; phosphatase mutant analysis; live-cell imaging; spindle assembly checkpoint assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in yeast, checkpoint functional assay, mechanistically extends prior Cdc14/Sli15 findings\",\n      \"pmids\": [\"20619650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ipl1 (Aurora B)-dependent phosphorylation of Sli15 (INCENP) prevents CPC binding to the preanaphase spindle and central spindle until late anaphase; decreased Ipl1-dependent Sli15 phosphorylation drives direct CPC binding to microtubules, influencing microtubule dynamics. Cdk1 and Ipl1/Aurora cooperatively modulate microtubule dynamics through Sli15 phosphorylation.\",\n      \"method\": \"Yeast genetics; phosphomutant analysis; microtubule dynamics measurements (live imaging); in vitro CPC-microtubule binding assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro binding assay combined with genetic phosphomutants and live-cell dynamics measurements, multiple orthogonal methods\",\n      \"pmids\": [\"21727193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of human Aurora B kinase domain in complex with human INCENP C-terminal region and inhibitor VX-680 reveals a dimeric arrangement of the Aurora B:INCENP complex confirmed by analytical ultracentrifugation; INCENP binding mode differs significantly from the Xenopus Aurora B:INCENP complex.\",\n      \"method\": \"X-ray crystallography; analytical ultracentrifugation\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of human complex validated by solution-phase ultracentrifugation, provides structural insight distinct from Xenopus model\",\n      \"pmids\": [\"22920039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of Xenopus Aurora B-INCENP complex with barasertib inhibitor reveals a crystal-packing contact where the INCENP C-terminus occupies the substrate-binding region of Aurora B, resembling a trans-inhibitory mechanism analogous to protein kinase A inhibition.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure observation only, potential crystal packing artifact not functionally validated\",\n      \"pmids\": [\"24598913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The central region of chicken INCENP (213 residues) is not a coiled coil but a ~32-nm-long single alpha-helix (SAH) domain; the N-terminal half of this SAH domain directly binds microtubules in vitro. The SAH domain acts as a flexible spacer ('dog leash') allowing Aurora B to reach outer kinetochore substrates while the CPC is anchored at the inner centromere.\",\n      \"method\": \"Biophysical analysis (CD spectroscopy, analytical ultracentrifugation); in vitro microtubule binding assays; mutagenesis; INCENP-knockout/rescue cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural characterization with multiple biophysical methods, in vitro microtubule binding, functional validation in cells, multiple orthogonal approaches\",\n      \"pmids\": [\"26175154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRMT1 arginine methyltransferase methylates INCENP at Arg887 in the Aurora B-binding IN-box region both in vitro and in vivo. R887-methylated INCENP shows lower binding affinity to Aurora B; PRMT1 knockdown or expression of methylation-inactive INCENP attenuates Aurora B activity and causes abnormal chromosome alignment/segregation.\",\n      \"method\": \"In vitro methylation assays; mass spectrometry; co-immunoprecipitation; kinase activity assays; chromosome segregation analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation with MS confirmation, functional consequence via Aurora B activity and mitotic phenotype, single lab\",\n      \"pmids\": [\"26460953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The putative coiled-coil domain within INCENP drives midzone localization of Aurora B via a direct electrostatic interaction with microtubules. The CPC multimerizes via INCENP's centromere-targeting (CEN box) domain, which increases microtubule-binding affinity. At anaphase onset, when H2AT120 is dephosphorylated, the microtubule-binding affinity outcompetes centromere affinity, switching CPC from centromere to microtubule localization.\",\n      \"method\": \"In vitro microtubule binding assays; multimerization assays; cell-based rescue experiments with INCENP mutants; phospho-H2A manipulation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding combined with cell-based mutant rescue, single lab, two orthogonal approaches\",\n      \"pmids\": [\"26166576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LATS1/2 kinases phosphorylate INCENP at Ser894 (within the TSS motif); this LATS-mediated phosphorylation is necessary and sufficient for Aurora B activation during cytokinesis in cells undergoing multipolar division.\",\n      \"method\": \"In vitro kinase assays; phosphomutant rescue experiments; Aurora B activity assays in cells; RNA interference\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation demonstrated, functional rescue with mutants, but single lab\",\n      \"pmids\": [\"27512725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"INCENP's actin-binding activity is important for cytokinesis and for midzone microtubule stabilization following furrow ingression; midzone microtubule stabilization depends on actomyosin contraction and Aurora B kinase activity, establishing a feedback between furrow ingression and microtubule dynamics mediated by the CPC.\",\n      \"method\": \"INCENP actin-binding mutant expression; live-cell imaging; Taxol rescue experiments; Aurora B inhibition\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — actin-binding mutant phenotype with pharmacological rescue, multiple imaging approaches, single lab\",\n      \"pmids\": [\"26898472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In addition to Survivin and Borealin, the SAH domain of INCENP supports CPC localization to chromatin and mitotic checkpoint function. INCENP SAH domain microtubule binding is negatively regulated by CDK-mediated phosphorylation of flanking segments. Dual recognition of chromatin and microtubules by INCENP is required for robust mitotic arrest.\",\n      \"method\": \"INCENP mutant rescue in Xenopus egg extracts and mammalian cells; microtubule binding assays; phosphomutant analysis; spindle checkpoint assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutants defining SAH domain functions, phosphorylation regulation shown, two model systems, multiple phenotypic readouts\",\n      \"pmids\": [\"28314740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In budding yeast, spindle association via the INCENP (Sli15) microtubule-binding domain is important for Aurora B (Ipl1) function in chromosome biorientation. Artificial dimerization of a minimal CPC (dimerized last-third of Sli15 + Ipl1) suppresses biorientation defects by promoting spindle association rather than by kinase clustering; a putative helical domain in Sli15 is required even when dimerized.\",\n      \"method\": \"Engineered minimal CPC with artificial dimerization (budding yeast); in vivo chromosome segregation assays; kinase activity measurements\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — elegant domain engineering approach, genetic rescue, single lab\",\n      \"pmids\": [\"28314741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The COMA inner kinetochore sub-complex physically interacts with Sli15 (INCENP) and recruits Ipl1-Sli15 (Aurora B-INCENP) to the inner kinetochore independently of Bir1 (survivin). Localization of Ipl1-Sli15 at centromeres or inner kinetochores is required for chromosome bi-orientation, established by engineered recruitment when both Bir1 and COMA are defective.\",\n      \"method\": \"Yeast genetics; co-immunoprecipitation; engineered kinetochore targeting; chromosome segregation assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical interaction by co-IP, sufficiency established by engineered targeting, genetic epistasis, multiple approaches\",\n      \"pmids\": [\"31006569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structures of the fully active AURKC:INCENP complex (with phosphorylated INCENP TSS motif) reveal that TSS motif phosphorylation stabilizes the kinase activation loop of AURKC and alters the substrate-binding surface, explaining the mechanism of synergistic Aurora C/B activation by INCENP phosphorylation. VX-680 inhibitor disrupts phosphorylated INCENP TSS motif binding.\",\n      \"method\": \"X-ray crystallography; biochemical kinase assays; native MS; thermal stability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of fully phosphorylated complex with biochemical validation, directly explains mechanism of synergistic activation, multiple structural and biochemical methods\",\n      \"pmids\": [\"31320618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phosphomimetic mutations of the INCENP STD-rich motif (phosphorylated by Plk1 in vitro and during mitosis in vivo) induce ectopic furrows and contractile ring formation in a Plk1- and ROCK1-dependent manner, independent of cell cycle and microtubule status. Non-phosphorylatable mutants cause chromosome congression failure and cytokinesis failure.\",\n      \"method\": \"INCENP conditional-knockout cell line; phosphomimetic and non-phosphorylatable mutant rescue; in vitro Plk1 kinase assay; live-cell imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation by Plk1 identified, rescue experiments in conditional KO cells, Plk1/ROCK1 inhibitor pharmacology, single lab\",\n      \"pmids\": [\"31601613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"An ATM-Chk2-INCENP pathway imposes the abscission checkpoint in response to chromatin bridges. ATM activates Chk2 at late midbodies; Chk2 phosphorylates human INCENP at Ser91, promoting INCENP binding to Mklp2 kinesin, which associates with Cep55 to localize the CPC to the midbody center and delay abscission. Nonphosphorylatable INCENP-Ser91A impairs CPC midbody localization and accelerates abscission; phosphomimetic INCENP-Ser91D rescues abscission delay in Chk2- or ATM-deficient cells.\",\n      \"method\": \"siRNA knockdown; phosphomimetic/non-phosphorylatable mutant rescue; co-immunoprecipitation; in vivo phosphorylation analysis; live-cell abscission imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-mutant rescue definitively links Chk2 phosphorylation of INCENP-Ser91 to Mklp2 binding and CPC midbody localization, multiple orthogonal methods, functional consequence established\",\n      \"pmids\": [\"33355621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Phosphorylation of INCENP's intrinsically disordered region (IDR) expands its conformation by increasing net charge, shifting the IDR from globular collapsed states to extended coil conformations. This phosphorylation-regulated length change modulates how Aurora B reaches its kinetochore targets, supporting the 'dog-leash' model.\",\n      \"method\": \"All-atom and coarse-grain molecular dynamics simulations of INCENP IDR with varying phosphorylation levels\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational simulations only, no experimental validation of the conformational transitions in this study\",\n      \"pmids\": [\"34883116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CryoEM structure of the CPC (Borealin-Survivin-INCENP) bound to H3Thr3-phosphorylated nucleosomes reveals multipartite interactions: N-terminus of Borealin and Survivin BIR domain act as pivot and flexible tethering points for CPC engagement at the nucleosome acidic patch and DNA entry-exit site. Perturbation of the CPC-nucleosome interaction compromises MNase protection in vitro and dynamic centromere association in cells, revealing a non-catalytic role for CPC in maintaining centromeric chromatin stability.\",\n      \"method\": \"CryoEM structure determination; atomic force microscopy; MNase protection assays; structure-based mutagenesis with cellular rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with biochemical and cellular validation, multiple methods, but preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"INCENP is the scaffold subunit of the chromosomal passenger complex (CPC; Aurora B/INCENP/Survivin/Borealin) that acts as a platform, activator, and localization determinant for Aurora B kinase: its N-terminal domain forms a three-helix bundle with Survivin and Borealin that targets the CPC to inner centromeres via H3Thr3-phosphorylated nucleosomes, its single-alpha-helix (SAH) central domain directly binds microtubules and acts as a flexible 'dog leash' allowing Aurora B to reach kinetochore substrates, and its C-terminal IN-box directly binds and allosterically activates Aurora B through a positive feedback loop in which Aurora B phosphorylates the INCENP TSS motif to achieve full kinase activation; CPC re-localization from centromeres to the spindle midzone at anaphase is triggered by dephosphorylation of INCENP by Cdc14 phosphatase (activated by separase), and additional regulatory inputs include Cdk1 phosphorylation of INCENP (controlling Plk1 recruitment), Chk2 phosphorylation of INCENP-Ser91 (imposing the abscission checkpoint via Mklp2 binding), and PRMT1 methylation of INCENP-Arg887 (reducing Aurora B binding affinity).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INCENP is the scaffold subunit of the chromosomal passenger complex (CPC), an evolutionarily conserved machine that coordinates chromosome segregation and cytokinesis by positioning and activating Aurora B kinase across mitosis; it localizes to the inner centromere through metaphase and then transfers to the central spindle, contractile ring, and midbody [#0, #3]. INCENP is modular: its N-terminal 58 residues form a three-helix bundle with Survivin and Borealin that is essential and sufficient to target the CPC to inner centromeres independently of Aurora B kinase activity [#19, #21], while its conserved C-terminal IN-box directly binds Aurora B (and the related Aurora C) and is required to localize the kinase to centromeres and the central spindle [#3, #15]. Binding within this complex allosterically activates Aurora B—the IN-box forms a crown around the kinase small lobe to induce the active T-loop conformation [#16]—and Aurora B in turn phosphorylates the INCENP TSS motif (Thr893/Ser894/Ser895), driving a positive-feedback loop that yields the fully active kinase [#10, #13, #37]. The central single-alpha-helix (SAH) domain of INCENP directly binds microtubules and acts as a flexible 'dog-leash' spacer that lets centromere-anchored Aurora B reach outer kinetochore substrates, with this microtubule affinity tuned by CDK phosphorylation of flanking segments [#29, #34]. Through these activities the CPC promotes chromosome bi-orientation by destabilizing erroneous kinetochore–microtubule attachments [#9], protects centromeric cohesion via substrates such as MEI-S332 [#20], and directs central-spindle and midbody assembly by recruiting kinesins MKLP1 and Plk1 [#17, #18]. Relocation from centromeres to the spindle midzone at anaphase is governed by INCENP phosphoregulation: Cdc14 phosphatase, activated by separase, dephosphorylates INCENP/Sli15 to trigger transfer and silence the mitotic checkpoint [#14, #25], and an electrostatic microtubule-binding switch coupled to H2A dephosphorylation drives the localization change [#31]. Additional regulatory inputs include Cdk1 phosphorylation controlling Plk1 recruitment [#17], Chk2 phosphorylation of Ser91 imposing the abscission checkpoint through Mklp2 binding [#39], and PRMT1 methylation of Arg887 that lowers Aurora B binding affinity [#30].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Established the existence and dynamic behavior of an inner centromere protein that relocates from chromosomes to the spindle and midbody, defining the phenomenon the gene is named for.\",\n      \"evidence\": \"Monoclonal antibody immunofluorescence and chromosome scaffold fractionation of mitotic cells\",\n      \"pmids\": [\"3316246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular partners or biochemical activity identified\", \"Mechanism of relocation unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapped INCENP into discrete functional modules, localizing centromere/midbody targeting to the N-terminus and revealing that centromere association is functionally coupled to downstream cytoskeletal events.\",\n      \"evidence\": \"GFP-tagged truncation/deletion mutagenesis, yeast two-hybrid, and dominant-negative expression in cultured cells\",\n      \"pmids\": [\"9864353\", \"9490714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HP1 interaction not linked to a function\", \"Microtubule region not yet characterized molecularly\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified INCENP as the direct binding partner and localization determinant for Aurora B kinase via the conserved C-terminal IN-box, defining the core of the CPC across species.\",\n      \"evidence\": \"Co-IP from Xenopus extracts, in vitro binding, co-localization, and C. elegans RNAi\",\n      \"pmids\": [\"10996078\", \"11050385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activation mechanism of Aurora B by INCENP not established\", \"Structural basis of IN-box binding unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed reciprocal interdependence of INCENP and Aurora B for localization/function and extended the complex to include Survivin and direct microtubule/tubulin binding by INCENP.\",\n      \"evidence\": \"Drosophila RNAi, yeast two-hybrid, in vitro tubulin/microtubule binding, dicentric chromosome imaging\",\n      \"pmids\": [\"11352945\", \"11516652\", \"11139336\", \"11734997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Centromere targeting dependence on cohesion only correlative\", \"Stoichiometry of multi-subunit complex unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the positive-feedback activation mechanism—Aurora B phosphorylates the INCENP C-terminus to potentiate its own kinase activity—and established Survivin-INCENP-Aurora B as a stable ternary complex.\",\n      \"evidence\": \"In vitro kinase assays with phosphosite mutagenesis (C. elegans), co-IP and gel filtration from Xenopus extracts, yeast bi-orientation genetics\",\n      \"pmids\": [\"12048181\", \"12221116\", \"11853667\", \"11809820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis of allosteric activation not yet known\", \"Quantitative activation thresholds undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Pinpointed the human INCENP TSS phosphosites (Thr893/Ser894/Ser895) whose phosphorylation drives Aurora B activation, and identified Cdc14-mediated INCENP dephosphorylation as the trigger coupling separase activation to anaphase CPC relocalization.\",\n      \"evidence\": \"Recombinant kinase assays with MS phosphosite mapping and mutagenesis (human); in vitro phosphatase assays and yeast genetics linking separase/Cdc14 to Sli15\",\n      \"pmids\": [\"12925766\", \"14605209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How relocalization silences the checkpoint not yet addressed\", \"Phosphatase regulation of human INCENP not directly shown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended INCENP's activating partnership to Aurora C, showing INCENP binds and activates a second Aurora kinase as part of a chromosomal passenger complex.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, transfection imaging in mammalian cells\",\n      \"pmids\": [\"15316025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context distinguishing Aurora B vs C unclear\", \"Structural basis of AURKC activation not shown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided the structural and regulatory logic of Aurora B activation by INCENP and defined Cdk1 phosphorylation of INCENP as a node controlling Plk1 recruitment and metaphase-to-anaphase timing.\",\n      \"evidence\": \"X-ray crystallography of Aurora B:IN-box; in vitro kinase assays and siRNA rescue with INCENP Cdk1-site mutants; co-IP\",\n      \"pmids\": [\"15866179\", \"16378098\", \"15796717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation states are spatially read out in vivo not resolved\", \"MKLP1 recruitment mechanism by INCENP not molecularly defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the minimal centromere-targeting module as a Survivin-Borealin-INCENP(N58) subcomplex and added a meiotic cohesion-protection role through MEI-S332 localization.\",\n      \"evidence\": \"Minimal subcomplex reconstitution with siRNA rescue; Drosophila incenp mutants with in vitro kinase/binding assays\",\n      \"pmids\": [\"16571674\", \"16824953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Centromeric receptor of the subcomplex not identified\", \"How targeting and cohesion protection are temporally coupled unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Solved the high-resolution structure of the Survivin-Borealin-INCENP regulatory core, explaining the structural interdependence of CPC subunits for localization.\",\n      \"evidence\": \"1.4 Å X-ray crystallography with siRNA rescue mutants and analytical ultracentrifugation; Dictyostelium actin-binding/Kif12 studies\",\n      \"pmids\": [\"17956729\", \"17567958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Connection between core structure and nucleosome engagement not yet known\", \"Actin-binding role conservation in vertebrates not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that graded Aurora B activity levels, set by INCENP C-terminal interactions and substoichiometric catalytic activation, partition distinct mitotic functions and define a kinetic activation mechanism.\",\n      \"evidence\": \"INCENP activity-mutant depletion/rescue with checkpoint assays; quantitative in vitro kinase kinetics\",\n      \"pmids\": [\"19951914\", \"18767990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial control of activity thresholds in cells not resolved\", \"Link between activity level and localization switch incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that Cdc14-mediated Sli15/INCENP dephosphorylation both relocates the CPC and silences the mitotic checkpoint after cohesin cleavage, establishing a conserved tension-loss bypass mechanism.\",\n      \"evidence\": \"Budding yeast genetics, phosphatase mutants, and checkpoint assays\",\n      \"pmids\": [\"20619650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical targets of dephosphorylation in human cells not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that Aurora B-dependent INCENP phosphorylation gates CPC-microtubule binding and that Cdk1 and Aurora cooperatively tune microtubule dynamics through INCENP phosphostate.\",\n      \"evidence\": \"Yeast phosphomutant genetics, live microtubule dynamics imaging, in vitro CPC-microtubule binding\",\n      \"pmids\": [\"21727193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the phospho-controlled microtubule switch not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Determined the human Aurora B:INCENP complex structure, revealing a dimeric arrangement and species-specific INCENP binding mode distinct from Xenopus.\",\n      \"evidence\": \"X-ray crystallography with analytical ultracentrifugation\",\n      \"pmids\": [\"22920039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of dimerization in vivo not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Captured a structural conformation in which the INCENP C-terminus occupies the Aurora B substrate site, hinting at a possible trans-inhibitory state.\",\n      \"evidence\": \"X-ray crystallography of Xenopus Aurora B-INCENP with inhibitor\",\n      \"pmids\": [\"24598913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Potential crystal-packing artifact not functionally validated\", \"No cellular evidence for trans-inhibition\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the central INCENP region as a single-alpha-helix microtubule-binding 'dog-leash' spacer and identified additional regulatory layers (electrostatic localization switch coupled to H2A dephosphorylation; PRMT1 methylation of Arg887 modulating Aurora B affinity).\",\n      \"evidence\": \"Biophysical SAH characterization with microtubule binding and rescue cell lines; in vitro multimerization/binding with phospho-H2A manipulation; in vitro methylation with MS and mitotic phenotyping\",\n      \"pmids\": [\"26175154\", \"26166576\", \"26460953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each affinity in vivo unresolved\", \"PRMT1 methylation findings from single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified LATS1/2 as an alternative INCENP TSS-motif kinase activating Aurora B during multipolar cytokinesis and linked INCENP actin binding to midzone microtubule stabilization feedback.\",\n      \"evidence\": \"In vitro kinase assays with phosphomutant rescue; actin-binding mutant live imaging with Taxol/Aurora B inhibition\",\n      \"pmids\": [\"27512725\", \"26898472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LATS1/2 role only shown in multipolar context, single lab\", \"Generality of actin-binding requirement across cell types unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the SAH domain contributes to chromatin localization and checkpoint function through dual chromatin/microtubule recognition, and that spindle association rather than kinase clustering underlies Aurora B's bi-orientation function.\",\n      \"evidence\": \"INCENP mutant rescue in Xenopus extracts and mammalian cells; engineered minimal/dimerized CPC in budding yeast with segregation assays\",\n      \"pmids\": [\"28314740\", \"28314741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise chromatin receptor for the SAH domain not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the structural mechanism by which TSS-motif phosphorylation fully activates Aurora kinases, identified an alternative kinetochore recruitment route via the COMA complex, and added Plk1 phosphorylation of the INCENP STD-rich motif as a furrow-inducing input.\",\n      \"evidence\": \"Crystal structures of phosphorylated AURKC:INCENP with biochemical assays; yeast genetics and engineered targeting (COMA); conditional-KO rescue with Plk1 phosphomutants\",\n      \"pmids\": [\"31320618\", \"31006569\", \"31601613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether COMA recruitment operates in vertebrates not shown\", \"Crosstalk between multiple INCENP phospho-inputs unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established an ATM-Chk2-INCENP-Ser91 axis that imposes the abscission checkpoint by promoting Mklp2-dependent CPC midbody localization, defining a DNA-damage-responsive cytokinesis control through INCENP.\",\n      \"evidence\": \"siRNA, phosphomimetic/non-phosphorylatable mutant rescue, co-IP, and live abscission imaging\",\n      \"pmids\": [\"33355621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How chromatin bridges activate ATM at the midbody not detailed\", \"Conformational basis of the dog-leash extension supported only computationally\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-catalytic, structural role for the CPC in maintaining centromeric chromatin stability via multipartite engagement of H3Thr3-phosphorylated nucleosomes.\",\n      \"evidence\": \"CryoEM, AFM, MNase protection, and structure-based mutagenesis with cellular rescue (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"In vivo consequences of chromatin stabilization for segregation fidelity incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple, often competing INCENP phospho- and methyl-regulatory inputs are integrated in space and time to switch the CPC between its sequential mitotic locations remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model coupling INCENP modifications to localization transitions\", \"Endogenous receptor(s) coordinating SAH-mediated chromatin/microtubule handoff not fully defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 13, 16, 24, 37]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 7, 17, 19, 39]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8, 29, 31]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [19, 21, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [8, 22, 29]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [19, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 3, 9, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12, 41]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\"Chromosomal passenger complex (CPC)\"],\n    \"partners\": [\"AURKB\", \"AURKC\", \"BIRC5\", \"CDCA8\", \"PLK1\", \"KIF20A\", \"KIF23\", \"HP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}