{"gene":"SKP1","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":1996,"finding":"SKP1 directly binds F-box proteins (Skp2, cyclin F, Cdc4p) through the F-box motif, and indirectly associates with cyclin A/Cdk2 through Skp2p. SKP1 is required for ubiquitin-mediated proteolysis of Cin2p, Clb5p, and the Cdk inhibitor Sic1p, establishing it as a core adaptor linking F-box substrate receptors to the ubiquitin proteolysis machinery.","method":"Yeast genetics (suppressor of cdc4 mutants), co-immunoprecipitation, two-hybrid, in vivo ubiquitination assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic suppression, Co-IP, two-hybrid, in vivo proteolysis assays), foundational study replicated extensively by subsequent work","pmids":["8706131"],"is_preprint":false},{"year":1996,"finding":"Budding yeast Skp1 is an intrinsic subunit of the CBF3 kinetochore complex that binds centromere DNA in vitro. Temperature-sensitive skp1 mutations cause two distinct arrest phenotypes: skp1-4 arrests in G2 with a short spindle (consistent with kinetochore defect), while skp1-3 arrests in G1, indicating distinct roles in kinetochore function and G1/S progression.","method":"Dosage suppressor screen, biochemical fractionation, centromere DNA-binding assay in vitro, temperature-sensitive mutant phenotyping","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical demonstration of CBF3 membership plus genetic dissection of two phenotypic classes in one rigorous study","pmids":["8706132"],"is_preprint":false},{"year":1998,"finding":"Human CUL-1 forms a trimeric complex with SKP1 and SKP2 (the SCF complex) in human cells. Antisense depletion of SKP1, SKP2, or CUL-1 causes selective accumulation of p21(CIP1/WAF1) and cyclin D proteins, identifying these as in vivo SCF targets.","method":"Co-immunoprecipitation, antisense oligodeoxynucleotide knockdown with Western blot readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional knockdown, single lab, two orthogonal approaches","pmids":["9736735"],"is_preprint":false},{"year":1998,"finding":"In budding yeast, Skp1 bridges Cdc53 (cullin) to three F-box proteins (Cdc4, Met30, Grr1) and Skp1 interacts with Cdc53 in vivo. Cdc53 contains independent binding sites for Cdc34 (E2) and Skp1, acting as a scaffold. Different F-box proteins show functional specificity: Cdc4 degrades Sic1, Grr1 degrades Cln2, Met30 represses methionine biosynthesis genes, while the Cdc34-Cdc53-Skp1 core is required for all three.","method":"Co-immunoprecipitation in vivo, genetic analysis of F-box protein-specific functions","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP combined with systematic genetic dissection of substrate specificity across multiple F-box proteins","pmids":["9499404"],"is_preprint":false},{"year":1998,"finding":"Human CUL1 directly interacts with hSKP1 and the F-box protein SKP2 in vitro to form an SCF-like particle. hCUL1 complements yeast cdc53(ts) mutants, associates with ubiquitination-promoting activity in human cell extracts, and assembles into functional chimeric ubiquitin ligase complexes with yeast SCF components.","method":"Yeast two-hybrid, in vitro binding assay, yeast complementation, ubiquitination activity assay in cell extracts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution, yeast complementation, and enzymatic activity assay in one study","pmids":["9636170"],"is_preprint":false},{"year":1999,"finding":"The F-box protein beta-Trcp associates with Skp1 and Cul1 to form an SCF complex that interacts with beta-catenin in vivo. A dominant-negative beta-Trcp stabilizes beta-catenin, identifying SCF(beta-Trcp) as the ubiquitin ligase mediating beta-catenin degradation.","method":"Co-immunoprecipitation, dominant-negative overexpression with Western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus dominant-negative functional evidence, single lab","pmids":["10023660"],"is_preprint":false},{"year":1999,"finding":"The SCF complex containing Skp1, Cul1, and F-box/WD40 protein HOS (FWD1 mouse homologue) specifically binds phosphorylated IkappaBalpha and beta-catenin. IkappaBalpha-E3 (containing Skp1, cullin-1, betaTrCP1 and betaTrCP2) catalyzes in vitro ubiquitination of phospho-IkappaBalpha in the presence of E1 and E2 enzymes.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, dominant-negative mutant expression","journal":"Oncogene / Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination reconstituted, replicated across two independent studies","pmids":["10321728","10066435"],"is_preprint":false},{"year":1999,"finding":"Residues 61-143 of Skp1 are required for binding to the F-box protein FWD1. Within the FWD1 F-box domain, Pro149, Ile160, and Leu164 are dispensable for Skp1 binding. In IkappaBalpha, an acidic residue at position 31 (in addition to phosphorylation at Ser32/Ser36) is required for FWD1-mediated ubiquitination.","method":"Deletion and point mutagenesis, co-immunoprecipitation, in vitro ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-function mutagenesis of both Skp1 and substrate binding interfaces combined with in vitro ubiquitination","pmids":["10514433"],"is_preprint":false},{"year":2000,"finding":"Crystal structure of human Skp2 bound to Skp1 reveals that Skp1 recruits F-box proteins through a bipartite interface involving both the F-box motif and the substrate-recognition domain of the F-box protein. The structure shows how Skp1 positions the F-box protein for substrate ubiquitination.","method":"X-ray crystallography","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with atomic resolution of the Skp1-F-box interface","pmids":["11099048"],"is_preprint":false},{"year":2001,"finding":"Skp1 forms multiple protein complexes in budding yeast beyond SCF, including RAVE (regulator of V-ATPase), which contains Skp1, Rav1, and Rav2. RAVE associates with the V1 domain of vacuolar H+-ATPase and promotes glucose-triggered assembly of the V-ATPase holoenzyme.","method":"Sequential affinity purification with mass spectrometry, biochemical reconstitution","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased mass spectrometry-based identification plus functional demonstration of V-ATPase assembly promotion","pmids":["11283612"],"is_preprint":false},{"year":2001,"finding":"Skp1/Skp2 complexes can be artificially redirected to ubiquitinate and degrade non-native substrate MetAP-2 when a bifunctional chimeric molecule (Protac-1) tethers the substrate to the SCF(beta-TRCP) complex via the IkappaBalpha phosphopeptide recognized by beta-TRCP F-box protein, demonstrating the modular substrate-recognition mechanism of SCF.","method":"In vitro ubiquitination assay with chimeric molecule, cell-based degradation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution plus cell-based degradation, demonstrates mechanistic modularity","pmids":["11438690"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of the full Cul1-Rbx1-Skp1-F-box(Skp2) SCF complex shows Cul1 as an elongated rigid scaffold connecting Skp1-Fbox(Skp2) substrate recognition complex at its tip to Rbx1 at its globular domain, with the two functional ends held >100 Å apart. Mutations designed to reduce scaffold rigidity impair ubiquitination activity.","method":"X-ray crystallography, structure-guided mutagenesis, ubiquitination activity assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure validated with mutagenesis and functional assay","pmids":["11961546"],"is_preprint":false},{"year":1998,"finding":"The cytoplasmic F-box binding protein SKP1 in Dictyostelium is modified post-translationally by a novel linear pentasaccharide (Galα1→6Galα1→Fucα1→2Galβ1→3GlcNAc) linked to hydroxyproline at Pro-143, representing an unusual cytoplasmic O-glycosylation.","method":"Mass spectrometry (quadrupole TOF), tandem MS, Edman degradation, GC-MS, exoglycosidase digestion","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical characterization by multiple MS methods with structural elucidation of the glycan","pmids":["9660787"],"is_preprint":false},{"year":2002,"finding":"CUL7 assembles a novel SCF-like E3 ubiquitin ligase complex containing Skp1, CUL7, the Fbx29 F-box protein, and ROC1. Unlike CUL1 which binds Skp1 alone, CUL7 interacts with the Skp1-Fbx29 complex but not Skp1 alone, and shows selectivity for Fbx29 but not betaTRCP2 or Skp2.","method":"Mass spectrometry (TAP), co-immunoprecipitation, in vitro binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based identification confirmed by Co-IP and in vitro binding, single lab","pmids":["12481031"],"is_preprint":false},{"year":1999,"finding":"Skp2 inhibits cyclin A-Cdk2 kinase activity in vitro, both by direct inhibition of the complex and by inhibiting CDK-activating kinase phosphorylation of Cdk2. The F-box of Skp2 is required for binding to Skp1, while both N- and C-terminal regions of Skp2 mediate binding to cyclin A-Cdk2. Skp2 and p21(Cip1) bind cyclin A-Cdk2 in a mutually exclusive manner.","method":"In vitro kinase assay, co-immunoprecipitation, mutagenesis, overexpression cell cycle analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase inhibition assay plus mutagenesis mapping, single lab","pmids":["9858587"],"is_preprint":false},{"year":2002,"finding":"In vivo interference with Skp1 function (by a dominant-negative Cul1-N252 mutant that sequesters Skp1) causes multinucleated cells, centrosome and mitotic spindle abnormalities, and impaired chromosome segregation. These phenotypes are rescued in double transgenic mice expressing both Cul1-N252 and wild-type Skp1, establishing a causal role for Skp1 in chromosomal segregation and genome stability.","method":"Transgenic mouse model, genetic epistasis (double transgenic rescue), cell biology (centrosome/spindle imaging)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis (double transgenic rescue) combined with detailed cellular phenotyping","pmids":["12417738"],"is_preprint":false},{"year":2005,"finding":"In Dictyostelium, Skp1 is hydroxylated at Pro143 by a cytoplasmic prolyl 4-hydroxylase (P4H1/PhyA) related to animal HIF-alpha class P4Hs. The enzyme requires O2, alpha-ketoglutarate, and ascorbate, is inhibited by CoCl2 and competitive substrates. Disruption of phyA blocks hydroxyproline-dependent glycosylation of Skp1 in vivo.","method":"Bioinformatics, gene disruption by homologous recombination, recombinant enzyme expression in E. coli, in vitro enzyme assay with [3H]GlcNAc transfer as readout, SDS-PAGE molecular weight shift","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted enzyme activity in vitro, gene disruption demonstrating in vivo requirement, multiple biochemical methods","pmids":["15705570"],"is_preprint":false},{"year":2006,"finding":"SKP1 interacts with CENP-E at the midbody via CENP-E's coiled-coil domain (residues 955-1571) and the C-terminal 33 amino acids of Skp1. siRNA-mediated suppression of Skp1 in mitotic HeLa cells results in accumulation of telophase cells with elongated inter-cell bridges and CENP-E accumulation, indicating that Skp1-mediated CENP-E degradation at the midbody is essential for cytokinesis.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro binding, siRNA knockdown with immunocytochemistry, overexpression of truncation mutant","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and two-hybrid with functional siRNA validation, single lab","pmids":["16682006"],"is_preprint":false},{"year":2011,"finding":"Skp1 assists in correct folding of F-box proteins (Fbs2, Fbg3, Fbg4, Fbg5): co-expression of Skp1 with these F-box proteins enables their binding to N-glycoprotein substrates and prevents aggregate formation, increasing F-box protein cellular concentrations. Skp1 thus stabilizes the conformation of F-box proteins.","method":"Co-expression with co-immunoprecipitation, glycoprotein binding assay (ConA), aggregation analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional co-expression with multiple F-box proteins, two assay types, single lab","pmids":["21640084"],"is_preprint":false},{"year":2012,"finding":"Assembly of the Skp1-F-box subcomplex with an F-box protein markedly inhibits CSN-mediated deneddylation of Cul1, with Fbw7-Skp1 inhibiting ~5-fold and Skp2-Cks1-Skp1 ~15%. Substrate addition further inhibits deneddylation ~2.5-fold. CSN can remain stably bound to deneddylated CRL and suppress its ubiquitin ligase activity by a non-catalytic mechanism.","method":"Kinetic enzyme assay (in vitro deneddylation), substrate addition experiments, quantitative biochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — detailed kinetic reconstitution in vitro with quantitative measurement of inhibition constants, single lab but multiple F-box substrates tested","pmids":["22767593"],"is_preprint":false},{"year":2013,"finding":"Substrate binding promotes formation of the SCF(Fbxl3) complex in vivo: Fbxl3 does not substantially associate with Skp1 and Cul1 unless its substrate Cry1 is co-expressed. An Fbxl3 mutant unable to bind Cry1 fails to form an SCF complex. In vitro, recombinant Fbxl3 associates with Skp1 and Cul1 without Cry1, suggesting an unknown inhibitory protein blocks complex formation in cells.","method":"Co-immunoprecipitation in mammalian cells, domain-swap analysis, in vitro reconstitution with recombinant proteins","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro approaches combined, contrasting results reveal a regulatory mechanism, single lab","pmids":["24085301"],"is_preprint":false},{"year":2014,"finding":"Glycosylation of Dictyostelium Skp1 at HyPro143 increases alpha-helical content, decreases beta-sheet content, and promotes a more compact and extended dimer conformation. Fully glycosylated Skp1 shows preferential binding to the mammalian F-box protein Fbs1 compared to unmodified Skp1, indicating glycosylation modulates F-box protein binding.","method":"Circular dichroism, small-angle X-ray scattering, analytical gel filtration, chemical cross-linking, in vitro F-box binding assay with purified recombinant proteins","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple biophysical methods (CD, SAXS, gel filtration) combined with direct binding assay using purified proteins","pmids":["24506136"],"is_preprint":false},{"year":2014,"finding":"In Dictyostelium, cells competent for full Skp1 glycosylation show greater abundance of SCF complexes containing CulE/FbxD and CulA/FbxA relative to cells defective in Skp1 hydroxylation or glycosylation. The CulE interactome includes higher levels of proteasomal regulatory particles in glycosylation-competent cells, suggesting increased SCF activity.","method":"Proteomic analysis of co-immunoprecipitates from wild-type vs. glycosylation mutants, mass spectrometry","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics across multiple mutants, single lab","pmids":["25341530"],"is_preprint":false},{"year":2017,"finding":"NMR and molecular dynamics simulations of Dictyostelium Skp1 show that the pentasaccharide glycan interacts with the loop connecting two alpha-helices of the F-box-combining site, causing the helices to separate and creating a more accessible, dynamic F-box interface. This mechanism explains how glycosylation enhances F-box protein interactions.","method":"NMR spectroscopy, molecular dynamics simulation, mass spectrometry for glycan structure","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure-function analysis with MD simulation validated by relaxation kinetics, mechanistically explains prior functional data","pmids":["28928219"],"is_preprint":false},{"year":2020,"finding":"SKP1 localizes to synapsed chromosome axes during meiotic prophase I in spermatocytes and is required for the PI/MI transition. SKP1-deficient spermatocytes show premature desynapsis, loss of PLK1 and BUB1 at centromeres, persistence of HORMAD, γH2AX, RPA2, and MLH1 in diplonema, sharply reduced MPF (CDK1) activity, and failure to enter meiosis I even after okadaic acid treatment. SKP1 also evicts HORMAD proteins from synapsed chromosome axes.","method":"Conditional Skp1 knockout mice, immunofluorescence localization, okadaic acid rescue experiment, CDK1 activity assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple molecular readouts (immunofluorescence, kinase activity, pharmacological rescue), demonstrates intrinsic metaphase competence factor role","pmids":["32232159"],"is_preprint":false},{"year":2009,"finding":"SKP1A silencing in dopaminergic neurons (SN4741 cells) causes delayed cell cycle completion, inability to arrest at G0/G1 upon differentiation, and formation of aggresome-like aggregates containing alpha-synuclein, ubiquitin, and proteasome subunits. Enforced SKP1A expression increases cell survival under proteasomal inhibition, suggesting a structural/protective role in dopaminergic neurons beyond E3 ligase activity.","method":"shRNA lentiviral knockdown, overexpression, cell cycle analysis, immunofluorescence for aggresome markers","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with defined cellular phenotypes and molecular readouts, single lab","pmids":["19748892"],"is_preprint":false},{"year":2010,"finding":"Human Hsp90-Sgt1 interacts with the Mis12 kinetochore complex. Co-inhibition of Sgt1 and the SCF subunit Skp1 increases Mis12 complex levels at kinetochores and restores timely chromosome alignment (relative to Sgt1 inhibition alone), but forms less-robust microtubule-binding sites, supporting a role for Skp1 in Mis12 complex turnover at kinetochores.","method":"Co-immunoprecipitation, siRNA double knockdown, kinetochore imaging, chromosome alignment assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by double siRNA knockdown with quantitative kinetochore imaging, single lab","pmids":["20404110"],"is_preprint":false},{"year":2015,"finding":"Small molecule 6-O-angeloylplenolin (6-OAP) binds directly to Skp1 at sites critical for Skp1-Skp2 interaction (and Skp1-beta-TRCP interaction), leading to dissociation of Skp2-SCF and beta-TRCP-SCF E3 ligases and accumulation of their substrates p27, E-cadherin, and Cyclin B1. Skp1 overexpression attenuates and Skp1 knockdown enhances these effects.","method":"Biotin-compound pulldown, mass spectrometry, co-immunoprecipitation, Skp1 KD/OE validation, in vivo xenograft models","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by biotin-pulldown/MS with KD/OE functional validation, single lab","pmids":["26474281"],"is_preprint":false},{"year":2021,"finding":"siRNA-mediated silencing of SKP1 (or CUL1) in fallopian tube secretory epithelial cells causes aberrant increases in Cyclin E1 protein levels and induces chromosome instability (CIN)-associated phenotypes including replication stress, DNA double-strand breaks, and chromothriptic events, mechanistically linking SKP1 to Cyclin E1 turnover and chromosome stability.","method":"siRNA knockdown, CRISPR/Cas9 deletion, quantitative imaging microscopy, Western blot for Cyclin E1","journal":"British journal of cancer / Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both siRNA and CRISPR approaches with multiple CIN readouts, consistent results across two studies","pmids":["33731859","32106628"],"is_preprint":false},{"year":2024,"finding":"A cysteine-reactive covalent recruiter (EN884) targeting SKP1 can be incorporated into PROTACs to degrade neo-substrate proteins (BRD4, androgen receptor) in a SKP1- and proteasome-dependent manner, demonstrating that the SKP1 adaptor protein within the SCF complex can serve as a direct PROTAC anchor for targeted protein degradation.","method":"Covalent chemoproteomic target identification, PROTAC synthesis, SKP1 siRNA knockdown, proteasome inhibition, Western blot","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct covalent binding demonstrated with functional PROTAC validation and genetic controls, single lab","pmids":["38305738"],"is_preprint":false},{"year":2024,"finding":"In C. elegans, two paralogous Skp1-related proteins (SKR-1 and SKR-2) serve as structural components of the synaptonemal complex (SC), repurposing their SCF-forming interfaces to dimerize and interact with meiosis-specific SC proteins, driving meiotic synapsis independently of SCF ubiquitin ligase activity. SKR-1 enables formation of a soluble complex with SC proteins in vitro, proposed to represent a complete SC building block.","method":"Genetic analysis (RNAi/mutants), in vitro reconstitution of SC building block, co-immunoprecipitation, super-resolution microscopy","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution plus genetic analysis with super-resolution microscopy, demonstrates moonlighting function","pmids":["38354250"],"is_preprint":false}],"current_model":"SKP1 is a conserved adaptor protein that serves as the core bridge within SCF (SKP1-Cullin1-F-box) E3 ubiquitin ligases, directly binding F-box proteins through their F-box motif and connecting them to Cullin1, thereby positioning diverse substrates for ubiquitination and proteasomal degradation; beyond SCF, SKP1 also functions as an intrinsic kinetochore component, interacts with CENP-E at the midbody to enable cytokinesis, acts as a metaphase competence factor during meiotic prophase I-to-metaphase I transition, stabilizes the conformation of F-box proteins, and in protists undergoes oxygen-regulated prolyl hydroxylation and cytoplasmic glycosylation at Pro143 that modulates F-box protein binding and SCF complex assembly."},"narrative":{"mechanistic_narrative":"SKP1 is a conserved adaptor protein that forms the core bridge of SCF (SKP1–Cullin1–F-box) E3 ubiquitin ligases, linking diverse F-box substrate-recognition proteins to the cullin scaffold to direct substrate ubiquitination and proteasomal degradation [PMID:8706131, PMID:9499404]. SKP1 binds F-box proteins through their F-box motif via a bipartite interface that engages both the F-box motif and the substrate-recognition domain, and it tethers them to Cullin1/Cdc53, which simultaneously positions the Rbx1 RING and E2 enzyme over the substrate held more than 100 Å away [PMID:8706131, PMID:11099048, PMID:11961546]. Through this modular architecture, SCF complexes built on distinct F-box receptors target specific substrates — Skp2-SCF degrades p21 and p27, SCF(β-TrCP) degrades phospho-IκBα and β-catenin, and SCF activity controls Cyclin E1 turnover [PMID:9736735, PMID:10321728, PMID:10066435, PMID:33731859, PMID:32106628]; the modularity is so general that engineered bifunctional molecules and covalent SKP1-targeting PROTACs can redirect SCF to degrade neo-substrates [PMID:11438690, PMID:38305738]. Beyond catalysis, SKP1 acts as a chaperone that stabilizes F-box protein conformation and prevents their aggregation [PMID:21640084], and SCF assembly is itself regulated — F-box subcomplex formation suppresses CSN-mediated deneddylation of Cul1, and substrate binding can promote complex assembly [PMID:22767593, PMID:24085301]. SKP1 also carries out SCF-independent roles in chromosome biology: it is required for chromosome segregation and genome stability [PMID:12417738], it controls CENP-E turnover at the midbody to permit cytokinesis [PMID:16682006], and it acts as an intrinsic metaphase-competence factor during meiotic prophase I, localizing to synapsed chromosome axes, evicting HORMAD proteins, and enabling the prophase-I-to-metaphase-I transition [PMID:32232159]. In Dictyostelium, SKP1 is hydroxylated at Pro143 by an O2-dependent prolyl 4-hydroxylase and further modified by a cytoplasmic pentasaccharide, a modification that reshapes the F-box-binding interface and tunes SCF complex assembly, providing an oxygen-sensing input to ubiquitin ligase activity [PMID:9660787, PMID:15705570, PMID:24506136, PMID:28928219].","teleology":[{"year":1996,"claim":"Established SKP1 as the adaptor that connects F-box substrate receptors to the ubiquitin-proteolysis machinery, defining its central function.","evidence":"Yeast genetics, Co-IP, two-hybrid, and in vivo ubiquitination assays identifying F-box binding and requirement for proteolysis of Sic1/Clb5/Cin2","pmids":["8706131"],"confidence":"High","gaps":["Did not resolve the structural basis of F-box binding","Cullin connection not yet defined"]},{"year":1996,"claim":"Revealed an SCF-independent role by showing SKP1 is an intrinsic CBF3 kinetochore subunit, separating its mitotic from its cell-cycle functions genetically.","evidence":"Dosage suppressor screen, biochemical fractionation, centromere DNA binding, and ts-mutant phenotyping in budding yeast","pmids":["8706132"],"confidence":"High","gaps":["Mechanism distinguishing kinetochore from proteolytic roles unresolved","Conservation of kinetochore role to metazoa not addressed"]},{"year":1998,"claim":"Defined the trimeric SCF architecture in both yeast and human cells, showing SKP1 bridges cullin to multiple F-box proteins with substrate specificity, and identified mammalian SCF targets.","evidence":"Reciprocal Co-IP, yeast complementation, antisense knockdown, and in vitro ubiquitination across yeast and human systems","pmids":["9499404","9636170","9736735"],"confidence":"High","gaps":["Substrate phosphodegron recognition not yet mapped","Catalytic geometry of the complex unknown"]},{"year":1999,"claim":"Mapped SCF(β-TrCP) as the ligase for phospho-IκBα and β-catenin and delineated the SKP1 region and substrate residues required for recognition and ubiquitination.","evidence":"Co-IP, dominant-negative expression, deletion/point mutagenesis, and in vitro ubiquitination reconstitution","pmids":["10023660","10321728","10066435","10514433"],"confidence":"High","gaps":["Atomic-resolution interface still lacking","Regulation of substrate phosphorylation upstream not addressed"]},{"year":2000,"claim":"Provided the atomic basis for how SKP1 grips F-box proteins, showing a bipartite interface that positions the substrate receptor for ubiquitination.","evidence":"X-ray crystallography of the Skp1–Skp2 complex","pmids":["11099048"],"confidence":"High","gaps":["Did not capture the full cullin-RING assembly","Dynamics of substrate handoff not visualized"]},{"year":2001,"claim":"Demonstrated SCF modularity and revealed SKP1 participates in non-SCF complexes, broadening its functional repertoire.","evidence":"Chimeric Protac-1 in vitro/cell ubiquitination assays and affinity-purification/MS identification of the RAVE complex","pmids":["11438690","11283612"],"confidence":"High","gaps":["Generality of non-SCF complexes in metazoa unclear","Functional importance of RAVE outside yeast not established"]},{"year":2002,"claim":"Resolved the elongated rigid SCF scaffold geometry and showed SKP1 contributes to genome stability in vivo, formally linking it to chromosome segregation.","evidence":"Full SCF crystal structure with structure-guided mutagenesis, plus transgenic-mouse double-transgenic rescue with cellular phenotyping","pmids":["11961546","12417738","12481031"],"confidence":"High","gaps":["Whether segregation defects are SCF-dependent or SCF-independent not fully separated","CUL7-specific substrates not defined"]},{"year":2014,"claim":"Established that SKP1 post-translational modification in Dictyostelium tunes F-box binding, defining an oxygen-sensing layer of SCF regulation.","evidence":"MS glycan elucidation, recombinant prolyl-hydroxylase assays, gene disruption, and biophysics (CD/SAXS) with F-box binding assays","pmids":["9660787","15705570","24506136","25341530"],"confidence":"High","gaps":["Whether equivalent modification operates in metazoan SKP1 unknown","Physiological O2 thresholds in vivo not quantified"]},{"year":2017,"claim":"Provided a structural mechanism for how glycosylation reshapes the F-box interface, explaining prior functional modulation data.","evidence":"NMR spectroscopy and molecular dynamics simulations of Dictyostelium Skp1","pmids":["28928219"],"confidence":"High","gaps":["Direct link to in vivo SCF flux not established","Generalizability beyond Dictyostelium unaddressed"]},{"year":2012,"claim":"Showed SKP1-F-box subcomplex assembly and substrate binding feed back on SCF activation by regulating deneddylation and complex formation.","evidence":"Kinetic deneddylation assays and Co-IP/in vitro reconstitution with Fbxl3/Cry1","pmids":["22767593","24085301"],"confidence":"High","gaps":["Identity of the cellular inhibitor blocking Fbxl3 assembly unknown","Quantitative contribution to substrate turnover in vivo unclear"]},{"year":2020,"claim":"Defined SKP1 as an intrinsic meiotic metaphase-competence factor acting at chromosome axes, extending its chromosome roles to meiosis.","evidence":"Conditional Skp1 knockout mice with immunofluorescence, CDK1 activity assay, and okadaic acid rescue; siRNA/CRISPR linking SKP1 to Cyclin E1 and chromosome instability","pmids":["32232159","33731859","32106628"],"confidence":"High","gaps":["Whether axis localization requires SCF activity not resolved","Direct ubiquitination targets at the axis unidentified"]},{"year":2024,"claim":"Demonstrated SKP1 can be repurposed as a structural synaptonemal-complex building block and as a covalent PROTAC anchor, illustrating both moonlighting biology and chemical exploitation.","evidence":"C. elegans genetics with in vitro SC reconstitution and super-resolution microscopy; covalent chemoproteomics with SKP1-anchored PROTACs and genetic controls","pmids":["38354250","38305738"],"confidence":"High","gaps":["Whether human SKP1 has an analogous SC structural role unknown","In vivo therapeutic window of SKP1 PROTACs untested"]},{"year":null,"claim":"How SKP1's SCF-dependent and SCF-independent (kinetochore, midbody, meiotic axis) functions are mechanistically partitioned, and whether metazoan SKP1 is regulated by modification, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model separating adaptor versus structural roles","Modification-based regulation of metazoan SKP1 uncharacterized","Direct substrates at chromosome structures undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,8,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,10,19]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[18]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,30]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,28]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1,24]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[24]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,15,28]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[24,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]}],"complexes":["SCF (SKP1-Cullin1-F-box) E3 ligase","CBF3 kinetochore complex","RAVE complex","synaptonemal complex"],"partners":["CUL1","SKP2","BTRC","CUL7","FBXL3","FBXW7","CENPE","RBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P63208","full_name":"S-phase kinase-associated protein 1","aliases":["Cyclin-A/CDK2-associated protein p19","p19A","Organ of Corti protein 2","OCP-2","Organ of Corti protein II","OCP-II","RNA polymerase II elongation factor-like protein","SIII","Transcription elongation factor B polypeptide 1-like","p19skp1"],"length_aa":163,"mass_kda":18.7,"function":"Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. 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SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO11) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2. Core component of the Cul7-RING(FBXW8) ubiquitin ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:35982156). 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PTAR1","url":"https://www.omim.org/entry/621024"},{"mim_id":"620870","title":"DNA DAMAGE-INDUCIBLE 1 HOMOLOG 1; DDI1","url":"https://www.omim.org/entry/620870"},{"mim_id":"620446","title":"TETRASPANIN 17; TSPAN17","url":"https://www.omim.org/entry/620446"},{"mim_id":"619746","title":"ZINC FINGER C3HC-TYPE DOMAIN-CONTAINING PROTEIN 1; ZC3HC1","url":"https://www.omim.org/entry/619746"},{"mim_id":"616008","title":"COP9 SIGNALOSOME, SUBUNIT 4; COPS4","url":"https://www.omim.org/entry/616008"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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SKP1 is required for ubiquitin-mediated proteolysis of Cin2p, Clb5p, and the Cdk inhibitor Sic1p, establishing it as a core adaptor linking F-box substrate receptors to the ubiquitin proteolysis machinery.\",\n      \"method\": \"Yeast genetics (suppressor of cdc4 mutants), co-immunoprecipitation, two-hybrid, in vivo ubiquitination assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic suppression, Co-IP, two-hybrid, in vivo proteolysis assays), foundational study replicated extensively by subsequent work\",\n      \"pmids\": [\"8706131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Budding yeast Skp1 is an intrinsic subunit of the CBF3 kinetochore complex that binds centromere DNA in vitro. Temperature-sensitive skp1 mutations cause two distinct arrest phenotypes: skp1-4 arrests in G2 with a short spindle (consistent with kinetochore defect), while skp1-3 arrests in G1, indicating distinct roles in kinetochore function and G1/S progression.\",\n      \"method\": \"Dosage suppressor screen, biochemical fractionation, centromere DNA-binding assay in vitro, temperature-sensitive mutant phenotyping\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical demonstration of CBF3 membership plus genetic dissection of two phenotypic classes in one rigorous study\",\n      \"pmids\": [\"8706132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human CUL-1 forms a trimeric complex with SKP1 and SKP2 (the SCF complex) in human cells. Antisense depletion of SKP1, SKP2, or CUL-1 causes selective accumulation of p21(CIP1/WAF1) and cyclin D proteins, identifying these as in vivo SCF targets.\",\n      \"method\": \"Co-immunoprecipitation, antisense oligodeoxynucleotide knockdown with Western blot readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional knockdown, single lab, two orthogonal approaches\",\n      \"pmids\": [\"9736735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"In budding yeast, Skp1 bridges Cdc53 (cullin) to three F-box proteins (Cdc4, Met30, Grr1) and Skp1 interacts with Cdc53 in vivo. Cdc53 contains independent binding sites for Cdc34 (E2) and Skp1, acting as a scaffold. Different F-box proteins show functional specificity: Cdc4 degrades Sic1, Grr1 degrades Cln2, Met30 represses methionine biosynthesis genes, while the Cdc34-Cdc53-Skp1 core is required for all three.\",\n      \"method\": \"Co-immunoprecipitation in vivo, genetic analysis of F-box protein-specific functions\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP combined with systematic genetic dissection of substrate specificity across multiple F-box proteins\",\n      \"pmids\": [\"9499404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human CUL1 directly interacts with hSKP1 and the F-box protein SKP2 in vitro to form an SCF-like particle. hCUL1 complements yeast cdc53(ts) mutants, associates with ubiquitination-promoting activity in human cell extracts, and assembles into functional chimeric ubiquitin ligase complexes with yeast SCF components.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, yeast complementation, ubiquitination activity assay in cell extracts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution, yeast complementation, and enzymatic activity assay in one study\",\n      \"pmids\": [\"9636170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The F-box protein beta-Trcp associates with Skp1 and Cul1 to form an SCF complex that interacts with beta-catenin in vivo. A dominant-negative beta-Trcp stabilizes beta-catenin, identifying SCF(beta-Trcp) as the ubiquitin ligase mediating beta-catenin degradation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression with Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus dominant-negative functional evidence, single lab\",\n      \"pmids\": [\"10023660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The SCF complex containing Skp1, Cul1, and F-box/WD40 protein HOS (FWD1 mouse homologue) specifically binds phosphorylated IkappaBalpha and beta-catenin. IkappaBalpha-E3 (containing Skp1, cullin-1, betaTrCP1 and betaTrCP2) catalyzes in vitro ubiquitination of phospho-IkappaBalpha in the presence of E1 and E2 enzymes.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, dominant-negative mutant expression\",\n      \"journal\": \"Oncogene / Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination reconstituted, replicated across two independent studies\",\n      \"pmids\": [\"10321728\", \"10066435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Residues 61-143 of Skp1 are required for binding to the F-box protein FWD1. Within the FWD1 F-box domain, Pro149, Ile160, and Leu164 are dispensable for Skp1 binding. In IkappaBalpha, an acidic residue at position 31 (in addition to phosphorylation at Ser32/Ser36) is required for FWD1-mediated ubiquitination.\",\n      \"method\": \"Deletion and point mutagenesis, co-immunoprecipitation, in vitro ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-function mutagenesis of both Skp1 and substrate binding interfaces combined with in vitro ubiquitination\",\n      \"pmids\": [\"10514433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Crystal structure of human Skp2 bound to Skp1 reveals that Skp1 recruits F-box proteins through a bipartite interface involving both the F-box motif and the substrate-recognition domain of the F-box protein. The structure shows how Skp1 positions the F-box protein for substrate ubiquitination.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with atomic resolution of the Skp1-F-box interface\",\n      \"pmids\": [\"11099048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Skp1 forms multiple protein complexes in budding yeast beyond SCF, including RAVE (regulator of V-ATPase), which contains Skp1, Rav1, and Rav2. RAVE associates with the V1 domain of vacuolar H+-ATPase and promotes glucose-triggered assembly of the V-ATPase holoenzyme.\",\n      \"method\": \"Sequential affinity purification with mass spectrometry, biochemical reconstitution\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased mass spectrometry-based identification plus functional demonstration of V-ATPase assembly promotion\",\n      \"pmids\": [\"11283612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Skp1/Skp2 complexes can be artificially redirected to ubiquitinate and degrade non-native substrate MetAP-2 when a bifunctional chimeric molecule (Protac-1) tethers the substrate to the SCF(beta-TRCP) complex via the IkappaBalpha phosphopeptide recognized by beta-TRCP F-box protein, demonstrating the modular substrate-recognition mechanism of SCF.\",\n      \"method\": \"In vitro ubiquitination assay with chimeric molecule, cell-based degradation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution plus cell-based degradation, demonstrates mechanistic modularity\",\n      \"pmids\": [\"11438690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of the full Cul1-Rbx1-Skp1-F-box(Skp2) SCF complex shows Cul1 as an elongated rigid scaffold connecting Skp1-Fbox(Skp2) substrate recognition complex at its tip to Rbx1 at its globular domain, with the two functional ends held >100 Å apart. Mutations designed to reduce scaffold rigidity impair ubiquitination activity.\",\n      \"method\": \"X-ray crystallography, structure-guided mutagenesis, ubiquitination activity assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure validated with mutagenesis and functional assay\",\n      \"pmids\": [\"11961546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The cytoplasmic F-box binding protein SKP1 in Dictyostelium is modified post-translationally by a novel linear pentasaccharide (Galα1→6Galα1→Fucα1→2Galβ1→3GlcNAc) linked to hydroxyproline at Pro-143, representing an unusual cytoplasmic O-glycosylation.\",\n      \"method\": \"Mass spectrometry (quadrupole TOF), tandem MS, Edman degradation, GC-MS, exoglycosidase digestion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical characterization by multiple MS methods with structural elucidation of the glycan\",\n      \"pmids\": [\"9660787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CUL7 assembles a novel SCF-like E3 ubiquitin ligase complex containing Skp1, CUL7, the Fbx29 F-box protein, and ROC1. Unlike CUL1 which binds Skp1 alone, CUL7 interacts with the Skp1-Fbx29 complex but not Skp1 alone, and shows selectivity for Fbx29 but not betaTRCP2 or Skp2.\",\n      \"method\": \"Mass spectrometry (TAP), co-immunoprecipitation, in vitro binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based identification confirmed by Co-IP and in vitro binding, single lab\",\n      \"pmids\": [\"12481031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Skp2 inhibits cyclin A-Cdk2 kinase activity in vitro, both by direct inhibition of the complex and by inhibiting CDK-activating kinase phosphorylation of Cdk2. The F-box of Skp2 is required for binding to Skp1, while both N- and C-terminal regions of Skp2 mediate binding to cyclin A-Cdk2. Skp2 and p21(Cip1) bind cyclin A-Cdk2 in a mutually exclusive manner.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, mutagenesis, overexpression cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase inhibition assay plus mutagenesis mapping, single lab\",\n      \"pmids\": [\"9858587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In vivo interference with Skp1 function (by a dominant-negative Cul1-N252 mutant that sequesters Skp1) causes multinucleated cells, centrosome and mitotic spindle abnormalities, and impaired chromosome segregation. These phenotypes are rescued in double transgenic mice expressing both Cul1-N252 and wild-type Skp1, establishing a causal role for Skp1 in chromosomal segregation and genome stability.\",\n      \"method\": \"Transgenic mouse model, genetic epistasis (double transgenic rescue), cell biology (centrosome/spindle imaging)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis (double transgenic rescue) combined with detailed cellular phenotyping\",\n      \"pmids\": [\"12417738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In Dictyostelium, Skp1 is hydroxylated at Pro143 by a cytoplasmic prolyl 4-hydroxylase (P4H1/PhyA) related to animal HIF-alpha class P4Hs. The enzyme requires O2, alpha-ketoglutarate, and ascorbate, is inhibited by CoCl2 and competitive substrates. Disruption of phyA blocks hydroxyproline-dependent glycosylation of Skp1 in vivo.\",\n      \"method\": \"Bioinformatics, gene disruption by homologous recombination, recombinant enzyme expression in E. coli, in vitro enzyme assay with [3H]GlcNAc transfer as readout, SDS-PAGE molecular weight shift\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted enzyme activity in vitro, gene disruption demonstrating in vivo requirement, multiple biochemical methods\",\n      \"pmids\": [\"15705570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SKP1 interacts with CENP-E at the midbody via CENP-E's coiled-coil domain (residues 955-1571) and the C-terminal 33 amino acids of Skp1. siRNA-mediated suppression of Skp1 in mitotic HeLa cells results in accumulation of telophase cells with elongated inter-cell bridges and CENP-E accumulation, indicating that Skp1-mediated CENP-E degradation at the midbody is essential for cytokinesis.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro binding, siRNA knockdown with immunocytochemistry, overexpression of truncation mutant\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and two-hybrid with functional siRNA validation, single lab\",\n      \"pmids\": [\"16682006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Skp1 assists in correct folding of F-box proteins (Fbs2, Fbg3, Fbg4, Fbg5): co-expression of Skp1 with these F-box proteins enables their binding to N-glycoprotein substrates and prevents aggregate formation, increasing F-box protein cellular concentrations. Skp1 thus stabilizes the conformation of F-box proteins.\",\n      \"method\": \"Co-expression with co-immunoprecipitation, glycoprotein binding assay (ConA), aggregation analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional co-expression with multiple F-box proteins, two assay types, single lab\",\n      \"pmids\": [\"21640084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Assembly of the Skp1-F-box subcomplex with an F-box protein markedly inhibits CSN-mediated deneddylation of Cul1, with Fbw7-Skp1 inhibiting ~5-fold and Skp2-Cks1-Skp1 ~15%. Substrate addition further inhibits deneddylation ~2.5-fold. CSN can remain stably bound to deneddylated CRL and suppress its ubiquitin ligase activity by a non-catalytic mechanism.\",\n      \"method\": \"Kinetic enzyme assay (in vitro deneddylation), substrate addition experiments, quantitative biochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — detailed kinetic reconstitution in vitro with quantitative measurement of inhibition constants, single lab but multiple F-box substrates tested\",\n      \"pmids\": [\"22767593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Substrate binding promotes formation of the SCF(Fbxl3) complex in vivo: Fbxl3 does not substantially associate with Skp1 and Cul1 unless its substrate Cry1 is co-expressed. An Fbxl3 mutant unable to bind Cry1 fails to form an SCF complex. In vitro, recombinant Fbxl3 associates with Skp1 and Cul1 without Cry1, suggesting an unknown inhibitory protein blocks complex formation in cells.\",\n      \"method\": \"Co-immunoprecipitation in mammalian cells, domain-swap analysis, in vitro reconstitution with recombinant proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro approaches combined, contrasting results reveal a regulatory mechanism, single lab\",\n      \"pmids\": [\"24085301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Glycosylation of Dictyostelium Skp1 at HyPro143 increases alpha-helical content, decreases beta-sheet content, and promotes a more compact and extended dimer conformation. Fully glycosylated Skp1 shows preferential binding to the mammalian F-box protein Fbs1 compared to unmodified Skp1, indicating glycosylation modulates F-box protein binding.\",\n      \"method\": \"Circular dichroism, small-angle X-ray scattering, analytical gel filtration, chemical cross-linking, in vitro F-box binding assay with purified recombinant proteins\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple biophysical methods (CD, SAXS, gel filtration) combined with direct binding assay using purified proteins\",\n      \"pmids\": [\"24506136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Dictyostelium, cells competent for full Skp1 glycosylation show greater abundance of SCF complexes containing CulE/FbxD and CulA/FbxA relative to cells defective in Skp1 hydroxylation or glycosylation. The CulE interactome includes higher levels of proteasomal regulatory particles in glycosylation-competent cells, suggesting increased SCF activity.\",\n      \"method\": \"Proteomic analysis of co-immunoprecipitates from wild-type vs. glycosylation mutants, mass spectrometry\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics across multiple mutants, single lab\",\n      \"pmids\": [\"25341530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NMR and molecular dynamics simulations of Dictyostelium Skp1 show that the pentasaccharide glycan interacts with the loop connecting two alpha-helices of the F-box-combining site, causing the helices to separate and creating a more accessible, dynamic F-box interface. This mechanism explains how glycosylation enhances F-box protein interactions.\",\n      \"method\": \"NMR spectroscopy, molecular dynamics simulation, mass spectrometry for glycan structure\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure-function analysis with MD simulation validated by relaxation kinetics, mechanistically explains prior functional data\",\n      \"pmids\": [\"28928219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SKP1 localizes to synapsed chromosome axes during meiotic prophase I in spermatocytes and is required for the PI/MI transition. SKP1-deficient spermatocytes show premature desynapsis, loss of PLK1 and BUB1 at centromeres, persistence of HORMAD, γH2AX, RPA2, and MLH1 in diplonema, sharply reduced MPF (CDK1) activity, and failure to enter meiosis I even after okadaic acid treatment. SKP1 also evicts HORMAD proteins from synapsed chromosome axes.\",\n      \"method\": \"Conditional Skp1 knockout mice, immunofluorescence localization, okadaic acid rescue experiment, CDK1 activity assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple molecular readouts (immunofluorescence, kinase activity, pharmacological rescue), demonstrates intrinsic metaphase competence factor role\",\n      \"pmids\": [\"32232159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SKP1A silencing in dopaminergic neurons (SN4741 cells) causes delayed cell cycle completion, inability to arrest at G0/G1 upon differentiation, and formation of aggresome-like aggregates containing alpha-synuclein, ubiquitin, and proteasome subunits. Enforced SKP1A expression increases cell survival under proteasomal inhibition, suggesting a structural/protective role in dopaminergic neurons beyond E3 ligase activity.\",\n      \"method\": \"shRNA lentiviral knockdown, overexpression, cell cycle analysis, immunofluorescence for aggresome markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with defined cellular phenotypes and molecular readouts, single lab\",\n      \"pmids\": [\"19748892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human Hsp90-Sgt1 interacts with the Mis12 kinetochore complex. Co-inhibition of Sgt1 and the SCF subunit Skp1 increases Mis12 complex levels at kinetochores and restores timely chromosome alignment (relative to Sgt1 inhibition alone), but forms less-robust microtubule-binding sites, supporting a role for Skp1 in Mis12 complex turnover at kinetochores.\",\n      \"method\": \"Co-immunoprecipitation, siRNA double knockdown, kinetochore imaging, chromosome alignment assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by double siRNA knockdown with quantitative kinetochore imaging, single lab\",\n      \"pmids\": [\"20404110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Small molecule 6-O-angeloylplenolin (6-OAP) binds directly to Skp1 at sites critical for Skp1-Skp2 interaction (and Skp1-beta-TRCP interaction), leading to dissociation of Skp2-SCF and beta-TRCP-SCF E3 ligases and accumulation of their substrates p27, E-cadherin, and Cyclin B1. Skp1 overexpression attenuates and Skp1 knockdown enhances these effects.\",\n      \"method\": \"Biotin-compound pulldown, mass spectrometry, co-immunoprecipitation, Skp1 KD/OE validation, in vivo xenograft models\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by biotin-pulldown/MS with KD/OE functional validation, single lab\",\n      \"pmids\": [\"26474281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"siRNA-mediated silencing of SKP1 (or CUL1) in fallopian tube secretory epithelial cells causes aberrant increases in Cyclin E1 protein levels and induces chromosome instability (CIN)-associated phenotypes including replication stress, DNA double-strand breaks, and chromothriptic events, mechanistically linking SKP1 to Cyclin E1 turnover and chromosome stability.\",\n      \"method\": \"siRNA knockdown, CRISPR/Cas9 deletion, quantitative imaging microscopy, Western blot for Cyclin E1\",\n      \"journal\": \"British journal of cancer / Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both siRNA and CRISPR approaches with multiple CIN readouts, consistent results across two studies\",\n      \"pmids\": [\"33731859\", \"32106628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A cysteine-reactive covalent recruiter (EN884) targeting SKP1 can be incorporated into PROTACs to degrade neo-substrate proteins (BRD4, androgen receptor) in a SKP1- and proteasome-dependent manner, demonstrating that the SKP1 adaptor protein within the SCF complex can serve as a direct PROTAC anchor for targeted protein degradation.\",\n      \"method\": \"Covalent chemoproteomic target identification, PROTAC synthesis, SKP1 siRNA knockdown, proteasome inhibition, Western blot\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct covalent binding demonstrated with functional PROTAC validation and genetic controls, single lab\",\n      \"pmids\": [\"38305738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In C. elegans, two paralogous Skp1-related proteins (SKR-1 and SKR-2) serve as structural components of the synaptonemal complex (SC), repurposing their SCF-forming interfaces to dimerize and interact with meiosis-specific SC proteins, driving meiotic synapsis independently of SCF ubiquitin ligase activity. SKR-1 enables formation of a soluble complex with SC proteins in vitro, proposed to represent a complete SC building block.\",\n      \"method\": \"Genetic analysis (RNAi/mutants), in vitro reconstitution of SC building block, co-immunoprecipitation, super-resolution microscopy\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution plus genetic analysis with super-resolution microscopy, demonstrates moonlighting function\",\n      \"pmids\": [\"38354250\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SKP1 is a conserved adaptor protein that serves as the core bridge within SCF (SKP1-Cullin1-F-box) E3 ubiquitin ligases, directly binding F-box proteins through their F-box motif and connecting them to Cullin1, thereby positioning diverse substrates for ubiquitination and proteasomal degradation; beyond SCF, SKP1 also functions as an intrinsic kinetochore component, interacts with CENP-E at the midbody to enable cytokinesis, acts as a metaphase competence factor during meiotic prophase I-to-metaphase I transition, stabilizes the conformation of F-box proteins, and in protists undergoes oxygen-regulated prolyl hydroxylation and cytoplasmic glycosylation at Pro143 that modulates F-box protein binding and SCF complex assembly.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SKP1 is a conserved adaptor protein that forms the core bridge of SCF (SKP1–Cullin1–F-box) E3 ubiquitin ligases, linking diverse F-box substrate-recognition proteins to the cullin scaffold to direct substrate ubiquitination and proteasomal degradation [#0, #3]. SKP1 binds F-box proteins through their F-box motif via a bipartite interface that engages both the F-box motif and the substrate-recognition domain, and it tethers them to Cullin1/Cdc53, which simultaneously positions the Rbx1 RING and E2 enzyme over the substrate held more than 100 Å away [#0, #8, #11]. Through this modular architecture, SCF complexes built on distinct F-box receptors target specific substrates — Skp2-SCF degrades p21 and p27, SCF(β-TrCP) degrades phospho-IκBα and β-catenin, and SCF activity controls Cyclin E1 turnover [#2, #6, #28]; the modularity is so general that engineered bifunctional molecules and covalent SKP1-targeting PROTACs can redirect SCF to degrade neo-substrates [#10, #29]. Beyond catalysis, SKP1 acts as a chaperone that stabilizes F-box protein conformation and prevents their aggregation [#18], and SCF assembly is itself regulated — F-box subcomplex formation suppresses CSN-mediated deneddylation of Cul1, and substrate binding can promote complex assembly [#19, #20]. SKP1 also carries out SCF-independent roles in chromosome biology: it is required for chromosome segregation and genome stability [#15], it controls CENP-E turnover at the midbody to permit cytokinesis [#17], and it acts as an intrinsic metaphase-competence factor during meiotic prophase I, localizing to synapsed chromosome axes, evicting HORMAD proteins, and enabling the prophase-I-to-metaphase-I transition [#24]. In Dictyostelium, SKP1 is hydroxylated at Pro143 by an O2-dependent prolyl 4-hydroxylase and further modified by a cytoplasmic pentasaccharide, a modification that reshapes the F-box-binding interface and tunes SCF complex assembly, providing an oxygen-sensing input to ubiquitin ligase activity [#12, #16, #21, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established SKP1 as the adaptor that connects F-box substrate receptors to the ubiquitin-proteolysis machinery, defining its central function.\",\n      \"evidence\": \"Yeast genetics, Co-IP, two-hybrid, and in vivo ubiquitination assays identifying F-box binding and requirement for proteolysis of Sic1/Clb5/Cin2\",\n      \"pmids\": [\"8706131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of F-box binding\", \"Cullin connection not yet defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Revealed an SCF-independent role by showing SKP1 is an intrinsic CBF3 kinetochore subunit, separating its mitotic from its cell-cycle functions genetically.\",\n      \"evidence\": \"Dosage suppressor screen, biochemical fractionation, centromere DNA binding, and ts-mutant phenotyping in budding yeast\",\n      \"pmids\": [\"8706132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing kinetochore from proteolytic roles unresolved\", \"Conservation of kinetochore role to metazoa not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the trimeric SCF architecture in both yeast and human cells, showing SKP1 bridges cullin to multiple F-box proteins with substrate specificity, and identified mammalian SCF targets.\",\n      \"evidence\": \"Reciprocal Co-IP, yeast complementation, antisense knockdown, and in vitro ubiquitination across yeast and human systems\",\n      \"pmids\": [\"9499404\", \"9636170\", \"9736735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate phosphodegron recognition not yet mapped\", \"Catalytic geometry of the complex unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapped SCF(β-TrCP) as the ligase for phospho-IκBα and β-catenin and delineated the SKP1 region and substrate residues required for recognition and ubiquitination.\",\n      \"evidence\": \"Co-IP, dominant-negative expression, deletion/point mutagenesis, and in vitro ubiquitination reconstitution\",\n      \"pmids\": [\"10023660\", \"10321728\", \"10066435\", \"10514433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution interface still lacking\", \"Regulation of substrate phosphorylation upstream not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Provided the atomic basis for how SKP1 grips F-box proteins, showing a bipartite interface that positions the substrate receptor for ubiquitination.\",\n      \"evidence\": \"X-ray crystallography of the Skp1–Skp2 complex\",\n      \"pmids\": [\"11099048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the full cullin-RING assembly\", \"Dynamics of substrate handoff not visualized\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated SCF modularity and revealed SKP1 participates in non-SCF complexes, broadening its functional repertoire.\",\n      \"evidence\": \"Chimeric Protac-1 in vitro/cell ubiquitination assays and affinity-purification/MS identification of the RAVE complex\",\n      \"pmids\": [\"11438690\", \"11283612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of non-SCF complexes in metazoa unclear\", \"Functional importance of RAVE outside yeast not established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved the elongated rigid SCF scaffold geometry and showed SKP1 contributes to genome stability in vivo, formally linking it to chromosome segregation.\",\n      \"evidence\": \"Full SCF crystal structure with structure-guided mutagenesis, plus transgenic-mouse double-transgenic rescue with cellular phenotyping\",\n      \"pmids\": [\"11961546\", \"12417738\", \"12481031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether segregation defects are SCF-dependent or SCF-independent not fully separated\", \"CUL7-specific substrates not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that SKP1 post-translational modification in Dictyostelium tunes F-box binding, defining an oxygen-sensing layer of SCF regulation.\",\n      \"evidence\": \"MS glycan elucidation, recombinant prolyl-hydroxylase assays, gene disruption, and biophysics (CD/SAXS) with F-box binding assays\",\n      \"pmids\": [\"9660787\", \"15705570\", \"24506136\", \"25341530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether equivalent modification operates in metazoan SKP1 unknown\", \"Physiological O2 thresholds in vivo not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided a structural mechanism for how glycosylation reshapes the F-box interface, explaining prior functional modulation data.\",\n      \"evidence\": \"NMR spectroscopy and molecular dynamics simulations of Dictyostelium Skp1\",\n      \"pmids\": [\"28928219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link to in vivo SCF flux not established\", \"Generalizability beyond Dictyostelium unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed SKP1-F-box subcomplex assembly and substrate binding feed back on SCF activation by regulating deneddylation and complex formation.\",\n      \"evidence\": \"Kinetic deneddylation assays and Co-IP/in vitro reconstitution with Fbxl3/Cry1\",\n      \"pmids\": [\"22767593\", \"24085301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the cellular inhibitor blocking Fbxl3 assembly unknown\", \"Quantitative contribution to substrate turnover in vivo unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined SKP1 as an intrinsic meiotic metaphase-competence factor acting at chromosome axes, extending its chromosome roles to meiosis.\",\n      \"evidence\": \"Conditional Skp1 knockout mice with immunofluorescence, CDK1 activity assay, and okadaic acid rescue; siRNA/CRISPR linking SKP1 to Cyclin E1 and chromosome instability\",\n      \"pmids\": [\"32232159\", \"33731859\", \"32106628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether axis localization requires SCF activity not resolved\", \"Direct ubiquitination targets at the axis unidentified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated SKP1 can be repurposed as a structural synaptonemal-complex building block and as a covalent PROTAC anchor, illustrating both moonlighting biology and chemical exploitation.\",\n      \"evidence\": \"C. elegans genetics with in vitro SC reconstitution and super-resolution microscopy; covalent chemoproteomics with SKP1-anchored PROTACs and genetic controls\",\n      \"pmids\": [\"38354250\", \"38305738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human SKP1 has an analogous SC structural role unknown\", \"In vivo therapeutic window of SKP1 PROTACs untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SKP1's SCF-dependent and SCF-independent (kinetochore, midbody, meiotic axis) functions are mechanistically partitioned, and whether metazoan SKP1 is regulated by modification, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model separating adaptor versus structural roles\", \"Modification-based regulation of metazoan SKP1 uncharacterized\", \"Direct substrates at chromosome structures undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 8, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 10, 19]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 28]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1, 24]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 15, 28]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [24, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\"SCF (SKP1-Cullin1-F-box) E3 ligase\", \"CBF3 kinetochore complex\", \"RAVE complex\", \"synaptonemal complex\"],\n    \"partners\": [\"CUL1\", \"SKP2\", \"BTRC\", \"CUL7\", \"FBXL3\", \"FBXW7\", \"CENPE\", \"RBX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}