Affinage

DYNLL1

Dynein light chain 1, cytoplasmic · UniProt P63167

Round 2 corrected
Length
89 aa
Mass
10.4 kDa
Annotated
2026-04-28
130 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DYNLL1 (LC8) is a highly conserved homodimeric hub protein that functions as a dimerization engine, binding short TQT-motif-containing linear sequences within intrinsically disordered regions of diverse scaffold proteins at its dimer interface to promote their oligomerization and regulate their activity (PMID:26226419, PMID:26652654). The DYNLL1 homodimer adopts a rectangular fold with a hydrophobic groove at the dimer interface where target peptides bind as an additional antiparallel β-strand; dimerization is required for cargo binding and is governed by a pH-sensitive histidine-dependent mechanism (PMID:10426949, PMID:11327818). Through this dimerization-driven mechanism, DYNLL1 controls apoptosis initiation by sequestering BH3-only protein Bim from Bcl-2 (PMID:10198631), gates autophagy by tethering the AMBRA1–BECLIN 1–VPS34 complex to the dynein motor until ULK1-mediated phosphorylation releases it (PMID:20921139), promotes axonal mitochondrial anchoring via syntaphilin (PMID:19641106), and governs DNA double-strand break repair pathway choice by binding MRE11 to suppress end resection and by driving 53BP1 oligomerization to promote NHEJ (PMID:30464262, PMID:30559443, PMID:37696958). DYNLL1 expression is regulated by a feedback loop in which the transcription factor ASCIZ activates the DYNLL1 promoter and DYNLL1 protein in turn inhibits ASCIZ transcriptional activity by binding multiple sites in its activation domain (PMID:22167198, PMID:32139510).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    The identification of DYNLL1 as a direct nNOS-binding protein that destabilizes the nNOS dimer and inhibits its enzymatic activity established DYNLL1's first function outside the dynein motor complex and raised the question of how a small dynein subunit could regulate unrelated enzymes.

    Evidence Yeast two-hybrid screen, co-immunoprecipitation, and functional nNOS activity assay in mammalian cells

    PMID:8864115

    Open questions at the time
    • Structural basis of nNOS dimer destabilization not resolved
    • In vivo physiological consequence of nNOS regulation by DYNLL1 not tested
  2. 1999 High

    Solving the crystal structure of the DYNLL1 homodimer with bound nNOS peptide revealed that target peptides bind as an antiparallel β-strand in a groove at the dimer interface, providing the structural framework that explained how DYNLL1 recognizes diverse partners through a shared binding mode.

    Evidence X-ray crystallography of DYNLL1–nNOS peptide complex

    PMID:10426949

    Open questions at the time
    • Only one partner peptide structure solved at this stage
    • How partner specificity is achieved with a common groove not yet addressed
  3. 1999 High

    The discovery that DYNLL1 sequesters the proapoptotic BH3-only protein Bim on the dynein motor and that apoptotic stimuli release Bim to neutralize Bcl-2 revealed a direct role for DYNLL1 in regulating programmed cell death, broadening its functional repertoire beyond motor-associated cargo transport.

    Evidence Co-immunoprecipitation, subcellular fractionation, and functional apoptosis assays

    PMID:10198631

    Open questions at the time
    • Mechanism of signal-dependent release of Bim from DYNLL1 not defined
    • Whether DYNLL1 binding to Bim is purely sequestration or also affects Bim conformation unclear
  4. 2001 High

    Biophysical characterization of the DYNLL1 monomer–dimer equilibrium and its pH-dependent regulation by histidine protonation established that dimerization is dynamically controlled and that the monomeric form cannot bind cargo, linking quaternary structure to functional competence.

    Evidence Analytical ultracentrifugation, size-exclusion chromatography, circular dichroism, and fluorescence spectroscopy on Drosophila LC8

    PMID:11327818 PMID:16385004

    Open questions at the time
    • Whether pH-driven monomer–dimer switching operates under physiological conditions in vivo not established
    • Post-translational regulation of the equilibrium not addressed
  5. 2003 High

    Demonstrating that JNK phosphorylation of Bim disrupts the DYNLL1–Bim complex connected the stress-activated MAPK pathway to the apoptotic gating function of DYNLL1, revealing the signaling logic upstream of Bim release.

    Evidence In vitro kinase assay, co-immunoprecipitation, genetic knockouts, and apoptosis assays

    PMID:12591950

    Open questions at the time
    • Whether JNK phosphorylation acts directly on the DYNLL1-binding motif or allosterically not resolved at atomic resolution
  6. 2007 High

    Structural comparison of DYNLL1 bound to dynein intermediate chain versus Swallow peptides showed that different partners compete for the same groove with differing affinities, supporting the emerging model that DYNLL1 acts as a general-purpose dimerization engine rather than exclusively a dynein cargo adaptor.

    Evidence X-ray crystallography, hydrogen–deuterium exchange NMR, and isothermal titration calorimetry on Drosophila LC8

    PMID:17570393

    Open questions at the time
    • How competition among partners is regulated in vivo not determined
    • Whether DYNLL1 binding always promotes dimerization or can serve other structural roles not fully resolved
  7. 2009 High

    The finding that DYNLL1 binds syntaphilin and stabilizes its microtubule-binding coiled-coil to anchor axonal mitochondria demonstrated a neuron-specific role for DYNLL1 in organelle positioning independent of the dynein motor, extending the dimerization-engine model to cytoskeletal anchoring.

    Evidence Co-immunoprecipitation, mutagenesis, time-lapse live imaging in neurons, and circular dichroism

    PMID:19641106

    Open questions at the time
    • Whether DYNLL1-dependent anchoring is regulated by neuronal activity not tested
    • Structural basis of SNPH coiled-coil stabilization at atomic level not resolved
  8. 2010 High

    Establishing that DYNLL1 tethers the AMBRA1–BECLIN 1–VPS34 autophagy initiation complex to the dynein motor and that ULK1 phosphorylation of AMBRA1 releases it revealed a DYNLL1-dependent cytoskeletal anchoring mechanism that gates autophagosome nucleation.

    Evidence Co-immunoprecipitation, subcellular fractionation, live-cell imaging, ULK1 kinase assay, and RNAi knockdown

    PMID:20921139

    Open questions at the time
    • Which DYNLL1-binding motif(s) in AMBRA1 are critical not mapped at residue level
    • Whether DYNLL1 contributes to autophagy regulation beyond AMBRA1 anchoring not explored
  9. 2011 High

    Discovery of the ASCIZ–DYNLL1 autoregulatory feedback loop, in which ASCIZ transcriptionally activates DYNLL1 and DYNLL1 inhibits ASCIZ by binding multiple sites in its activation domain, resolved how cellular DYNLL1 levels are homeostatically maintained.

    Evidence ChIP, reporter assays, co-immunoprecipitation, and shRNA knockdown across human, mouse, and chicken cells

    PMID:22167198

    Open questions at the time
    • How the system responds to acute perturbations (e.g. DNA damage) not addressed
    • Whether other transcription factors contribute to DYNLL1 expression not tested
  10. 2014 High

    Structural and biophysical demonstration that DYNLL1 dimers assemble the centriole duplication factor Ana2 into tetramers via two binding motifs confirmed DYNLL1's function as a multivalent dimerization engine that can organize higher-order oligomeric complexes in centriole biogenesis.

    Evidence X-ray crystallography (two structures), ITC, and SEC-MALS on Drosophila Ana2–LC8

    PMID:24920673

    Open questions at the time
    • Functional consequence of LC8-driven Ana2 oligomerization on centriole duplication in vivo not directly tested in this study
  11. 2015 High

    Crystal structures of DYNLL1 bound to Chica peptides revealed an 'anchored flexibility' recognition model in which the invariant TQT triplet provides a rigid anchor while flanking residues adopt variable conformations, explaining how a single groove accommodates the large diversity of DYNLL1 partners.

    Evidence X-ray crystallography, NMR relaxation, and ITC

    PMID:26652654

    Open questions at the time
    • How post-translational modifications of flanking residues modulate affinity not explored
    • Structural basis for motif context preferences beyond TQT not fully defined
  12. 2015 High

    The demonstration that Ebola VP35 and rabies virus phosphoprotein hijack DYNLL1 dimerization to stabilize their oligomerization domains and enhance viral polymerase activity extended the dimerization-engine paradigm to host–pathogen interactions and identified DYNLL1 as a pro-viral host factor.

    Evidence Pull-down, mutagenesis, viral RNA synthesis assay (Ebola VP35); NMR, SAXS ensemble structure, polymerase assay (rabies phosphoprotein)

    PMID:25741013 PMID:31634467

    Open questions at the time
    • Whether therapeutic disruption of DYNLL1–viral protein interactions is feasible without compromising host functions not addressed
    • Generality across other viral families not systematically tested
  13. 2018 High

    A genome-wide CRISPR screen and biochemical reconstitution revealed that DYNLL1 directly binds MRE11, limits DNA end resection, and thereby controls the balance between NHEJ and homologous recombination; loss of DYNLL1 restores HR in BRCA1-mutant cells and induces PARP inhibitor resistance, establishing DYNLL1 as a critical regulator of DSB repair pathway choice.

    Evidence Genome-wide CRISPR screen, in vitro DNA resection assay with purified proteins, co-immunoprecipitation, HR reporter assays, and drug sensitivity assays

    PMID:30464262

    Open questions at the time
    • Whether DYNLL1 disrupts the MRE11 dimer directly or acts allosterically not structurally defined
    • Contribution of DYNLL1 to repair pathway choice in normal (BRCA1-proficient) cells not fully explored
  14. 2018 High

    Parallel work showed that DYNLL1 promotes 53BP1 oligomerization and chromatin association, stimulating NHEJ and class switch recombination; this complemented the MRE11-based anti-resection function by revealing a second, reinforcing arm of DYNLL1 action at DSBs.

    Evidence Co-immunoprecipitation, chromatin fractionation, CSR assays, PARP inhibitor sensitivity, and DYNLL1-binding motif mutagenesis in 53BP1

    PMID:30559443

    Open questions at the time
    • Stoichiometry of DYNLL1 within the 53BP1 oligomeric complex not quantified
    • Whether DYNLL1-driven 53BP1 oligomerization is sufficient for NHEJ or requires additional co-factors not resolved
  15. 2019 High

    Proteomic phage display identified 29 validated DYNLL1-binding peptides across the human proteome and established that residues flanking the TQT anchor critically determine binding competence, dramatically expanding the known interactome and providing a predictive algorithm (LC8Pred).

    Evidence Proteomic phage display with ITC validation of 29 peptides

    PMID:31266884

    Open questions at the time
    • Many predicted interactions lack cellular validation
    • Whether all validated peptides mediate dimerization or serve alternative functions not tested
  16. 2023 High

    Temporal dissection of DSB repair showed that DYNLL1 is recruited to breaks early via 53BP1 where it disrupts MRE11 dimers to suppress resection, with Shieldin arriving later and depending on DYNLL1–MRE11 activity, defining the hierarchical order of the anti-resection machinery and explaining how constitutive DYNLL1–MRE11 association can resensitize Shieldin-deficient BRCA1-mutant cells to PARP inhibitors.

    Evidence Live-cell imaging, proximity ligation assay, co-immunoprecipitation, genetic knockouts, and PARP inhibitor sensitivity assays with cell-cycle resolution

    PMID:37696958

    Open questions at the time
    • Structural basis of DYNLL1-mediated MRE11 dimer disruption not yet solved
    • Whether additional DYNLL1 partners contribute to DSB repair independently of 53BP1 and MRE11 not excluded

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include how the competition among DYNLL1's many partners is prioritized in different cellular contexts, whether post-translational modifications beyond phosphorylation regulate the monomer–dimer equilibrium in vivo, and whether the DYNLL1–MRE11 interaction can be therapeutically targeted to overcome PARP inhibitor resistance without compromising essential DYNLL1 functions.
  • No in vivo partner competition model exists
  • Post-translational regulation of DYNLL1 dimerization beyond pH and phosphorylation is unexplored
  • Therapeutic window for targeting DYNLL1 in DNA repair not assessed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 7 GO:0005198 structural molecule activity 5 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005694 chromosome 4 GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005856 cytoskeleton 3
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-168256 Immune System 1 R-HSA-9612973 Autophagy 1
Partners
AMBRA1ASCIZBIMMRE11NOS1PAK1SNPHTP53BP1
Complex memberships
53BP1 anti-resection complexCytoplasmic dynein complexPICTS piRNA silencing complex (Drosophila)

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 PIN (DYNLL1/LC8) was identified as a protein that physically interacts with neuronal nitric oxide synthase (nNOS) via yeast two-hybrid screening and destabilizes the nNOS dimer, thereby inhibiting its enzymatic activity. This established DYNLL1 as a regulator of nNOS and the first characterized binding partner outside the dynein motor complex. Yeast two-hybrid screen, co-immunoprecipitation, functional nNOS activity assay Science High 8864115
1999 The proapoptotic BH3-only protein Bim is sequestered in healthy cells by binding to dynein LC8 (DYNLL1), tethering it to the microtubule-associated dynein motor complex. Apoptotic stimuli disrupt the LC8–dynein motor interaction, freeing Bim to translocate to Bcl-2 and neutralize its antiapoptotic activity, identifying DYNLL1 as a regulator of apoptosis initiation. Co-immunoprecipitation, subcellular fractionation, functional apoptosis assays Molecular Cell High 10198631
1999 Crystal structure of the PIN/LC8 (DYNLL1) dimer was solved at atomic resolution, revealing a rectangular homodimer with two pairs of alpha-helices flanking a five-stranded antiparallel beta-sheet. A 13-residue peptide from nNOS binds in a deep hydrophobic groove at the dimer interface as a sixth antiparallel beta-strand, providing the structural basis for dimerization and peptide binding. X-ray crystallography Nature Structural Biology High 10426949
2001 Drosophila LC8 (ortholog of DYNLL1) forms a reversible monomer–dimer equilibrium with a dissociation constant of 12 µM at pH 7; at pH below ~4.8, LC8 dissociates to a folded monomer that retains secondary and tertiary structure but loses quaternary structure. The dimer interface involves a histidine pair whose protonation drives dissociation, establishing a pH-dependent mechanism for dynein complex regulation. Analytical ultracentrifugation, size-exclusion chromatography, circular dichroism, fluorescence spectroscopy Biochemistry High 11327818
2003 JNK phosphorylates Bim (and Bmf), causing release of Bim from its sequestration by dynein LC8 (DYNLL1), thereby linking the JNK stress signaling pathway to Bax/Bak-dependent mitochondrial apoptosis. This demonstrated that phosphorylation-dependent regulation of DYNLL1–Bim interaction is a key upstream apoptotic event. In vitro kinase assay, co-immunoprecipitation, genetic knockouts, apoptosis assays Proceedings of the National Academy of Sciences of the United States of America High 12591950
2005 The pH-dependent dimer-to-monomer transition of DLC8 (DYNLL1) involves stepwise structural changes: at pH 5–7, partial protonation of histidines causes conformational dynamics and partial loosening of the dimeric structure, whereas below pH 5, charge repulsions, loss of hydrophobic interactions, and destabilization of hydrogen bonds across the dimer interface cause full dissociation. The monomeric form does not bind target proteins, establishing that dimerization is required for cargo binding. 15N NMR transverse relaxation measurements, line broadening analysis, pH titration Protein Science High 16385004
2007 Crystal structures of Drosophila LC8 (DYNLL1 ortholog) bound to peptides from dynein intermediate chain (IC) and Swallow showed that both peptides bind in the same grooves at the dimer interface, despite sharing the KXTQT recognition sequence. Swallow binds with higher affinity than IC, suggesting that LC8's primary function in the context of Swallow is as a dimerization engine rather than a cargo adaptor for dynein. X-ray crystallography, hydrogen–deuterium exchange NMR, isothermal titration calorimetry Journal of Molecular Biology High 17570393
2008 Biochemical, NMR, and crystallographic studies showed that Pak1 (residues 212–222) binds to LC8 (DYNLL1) along the same dimer-interface groove as canonical partners (e.g., nNOS, BimL). The target-binding interface requires LC8 dimerization, which precludes phosphorylation of LC8 at Ser88, disproving the model that Pak1 phosphorylates LC8 to promote anchorage-independent growth; instead, LC8 binding modulates Pak1 activity and/or localization. NMR chemical shift mapping, X-ray crystallography, in vitro phosphorylation assay, LC8 point mutagenesis The Journal of Biological Chemistry High 18650427
2008 NMR backbone 15N relaxation experiments showed that monomeric LC8 (modeled by H55K mutant) has more heterogeneous dynamics than the dimer, particularly in residues forming the binding groove (β1 and β3 strands), suggesting that conformations primed for binding are sampled in the inactive monomer and stabilized in the active dimer. Peptide binding from Swallow causes more ordering than IC binding, correlating with less favorable binding entropy for Swallow. 15N NMR relaxation (T1, T2), equilibrium unfolding Biochemistry High 18942858
2009 LC8 (DYNLL1) binds directly to syntaphilin (SNPH) via a seven-residue LC8-binding motif, recruiting LC8 to axonal mitochondria and enhancing the SNPH–microtubule docking interaction, thereby reducing mitochondrial mobility. LC8 stabilizes an alpha-helical coiled-coil within the microtubule-binding domain of SNPH, explaining how LC8 promotes mitochondrial anchoring in axons. Co-immunoprecipitation, mutagenesis mapping, time-lapse live imaging in neurons, circular dichroism thermal stability assay The Journal of Neuroscience High 19641106
2009 LC8 (DYNLL1) interaction with Pak1 (via LC8-binding site adjacent to the Pak1 NLS) mediates LC8-dependent dimerization of Pak1, which is required for EGF-induced nuclear import of Pak1 in MCF-7 cells. Pak2, which lacks an LC8-binding site, remains cytoplasmic. In zebrafish, developmental defects caused by Pak morpholino knockdown were only partially rescued by wild-type Pak1, not by Pak1 mutants lacking the LC8-binding or NLS sites. Co-immunoprecipitation, subcellular fractionation, EGF stimulation assays, zebrafish morpholino rescue experiments PloS One High 19557173
2010 AMBRA1 (a BECLIN 1-interacting protein) is tethered to the cytoskeleton through interaction with dynein light chains 1 and 2 (including DYNLL1). Upon autophagy induction, ULK1 phosphorylates AMBRA1, releasing the BECLIN 1-VPS34 autophagy core complex from dynein. The complex then relocalizes to the endoplasmic reticulum, enabling autophagosome nucleation, demonstrating that DYNLL1-mediated cytoskeletal anchoring gates autophagy initiation. Co-immunoprecipitation, subcellular fractionation, live-cell imaging, ULK1 kinase assay, RNAi knockdown The Journal of Cell Biology High 20921139
2011 ASCIZ (ATMIN/ZNF822) was identified as a transcriptional activator that directly binds the Dynll1 promoter in a zinc-finger-dependent manner and is required for DYNLL1 expression (DYNLL1 levels drop ~10-fold without ASCIZ). DYNLL1 protein in turn interacts with ten binding sites in the ASCIZ transcription activation domain, inhibiting ASCIZ transcriptional activity at high DYNLL1 levels. This establishes a feedback loop where ASCIZ activates Dynll1 gene expression and DYNLL1 suppresses ASCIZ activity, auto-regulating gene expression. ChIP, reporter assays, Co-IP, shRNA knockdown in human/mouse/chicken cells The Journal of Biological Chemistry High 22167198
2011 LC8 (DYNLL1) was shown to bind tubulin, promote microtubule assembly in vitro, stabilize microtubules against cold- and nocodazole-induced depolymerization, increase microtubule acetylation in cells, and promote microtubule bundling both in vitro and in HeLa cells and Drosophila embryos. LC8 knockdown or inhibitory peptides destabilize microtubules and inhibit bipolar spindle assembly, causing mitotic block, establishing a novel MAP-like function for DYNLL1. In vitro microtubule assembly assay, fluorescence microscopy in Drosophila embryos and HeLa cells, siRNA knockdown, nocodazole/cold depolymerization assay, molecular docking The Journal of Biological Chemistry Medium 23038268
2014 LC8 (DYNLL1 ortholog) mediates oligomerization of the Drosophila centriole duplication factor Ana2 by binding two sites in Ana2 (a canonical TQT-containing site with KD ~1.1 µM and a TQC-containing site with KD ~13 µM). Crystal structures showed Ana2 peptides extending the LC8 beta-sandwich. LC8 dimers induce Ana2 tetramerization (Ana2M4-LC88 complex), likely enhancing Ana2 avidity for centriole-binding factors during spindle positioning and centriole biogenesis. Isothermal titration calorimetry, X-ray crystallography (two structures), size-exclusion chromatography–multi-angle light scattering The Journal of Biological Chemistry High 24920673
2015 Ebola virus VP35 directly interacts with dynein LC8 (DYNLL1) with high affinity; LC8 binding stabilizes the VP35 N-terminal oligomerization domain and enhances viral RNA synthesis. Mutational analysis demonstrated that the VP35–LC8 interaction is required for these functional effects, identifying DYNLL1 as a host factor hijacked to promote Ebola virus replication. Direct binding assay (pull-down), mutagenesis, viral RNA synthesis assay Journal of Virology High 25741013
2015 LC8 (DYNLL1) functions as a hub protein that promotes dimerization of intrinsically disordered protein (IDP) scaffold partners by binding short linear TQT-motif-containing sequences in disordered regions. LC8 dimers bridge two IDP chains in parallel (IDP duplex scaffolds), as exemplified by dynein intermediate chain and nucleoporin Nup159, forming assemblies with enhanced avidity for additional bivalent ligands. NMR, analytical ultracentrifugation, isothermal titration calorimetry, structural analysis of existing complexes FEBS Letters High 26226419
2015 Crystal structures of LC8 (DYNLL1) bound to two Chica spindle adaptor motif peptides revealed that TQT-LC8 interactions are rigid and invariant (acting as anchors), while non-TQT interactions are flexible and conformationally variable. This 'anchored flexibility' model explains both the requirement for the TQT triplet and the ability of LC8 to accommodate diverse motif sequences with varying affinities. X-ray crystallography (two structures), NMR (chemical shifts, relaxation), isothermal titration calorimetry Biochemistry High 26652654
2018 DYNLL1 was identified by a loss-of-function CRISPR screen as an inhibitor of DNA end resection. In vitro, DYNLL1 binds directly to MRE11 and limits its end-resection nuclease activity. In cells, DYNLL1 associates with the DNA end-resection machinery (MRN complex, BLM helicase, DNA2 endonuclease). Loss of DYNLL1 restores homologous recombination in BRCA1-mutant cells and induces resistance to platinum drugs and PARP inhibitors. Genome-wide CRISPR loss-of-function screen, in vitro DNA resection assay with purified proteins, Co-IP, cell-based HR assays, drug sensitivity assays Nature High 30464262
2018 DYNLL1 promotes 53BP1 oligomerization and stimulates 53BP1 recruitment to and interaction with DSB-associated chromatin. DYNLL1 organizes multimeric 53BP1 complexes and regulates 53BP1-dependent NHEJ: deletion of Dynll1 or mutation of DYNLL1-binding motifs in 53BP1 compromises class switch recombination. Deletion of Dynll1 in BRCA1-mutant cells renders them resistant to PARP inhibitor treatment. Co-immunoprecipitation, chromatin fractionation, class switch recombination assays, PARP inhibitor sensitivity assays, DYNLL1-binding motif mutagenesis, genetic deletion Nature Communications High 30559443
2018 DYNLL1 forms a high-affinity 2:2 heterotetramer with the cytoplasmic domain of L-MAG (large myelin-associated glycoprotein). Crystal structure of the complex shows DYNLL1 binding close to the L-MAG C-terminus, next to the Fyn kinase phosphorylation site, in a parallel arrangement distinct from previously characterized DYNLL1 ligand complexes. This interaction is isoform-specific (L-MAG but not S-MAG) and is proposed to mediate L-MAG dimerization affecting myelin-to-axon adhesion and signalling. Yeast two-hybrid screening, in vitro binding with recombinant proteins, X-ray crystallography, small-angle X-ray scattering (SAXS) Journal of Neurochemistry High 30261098
2019 LC8 (DYNLL1) accumulates at laser-induced DNA damage tracks in a 53BP1-dependent manner, requiring the canonical H2AX-MDC1-RNF8-RNF168 signal transduction cascade for recruitment. Genetic inactivation of LC8 or disruption of its interaction with 53BP1 causes checkpoint defects and alleviates hypersensitivity of BRCA1-depleted cells to ionizing radiation and PARP inhibition, establishing LC8 as a 53BP1 effector in DSB checkpoint activation. Laser-induced DNA damage imaging, Co-IP, genetic inactivation, checkpoint assays, PARP inhibitor sensitivity assays Nucleic Acids Research High 30982887
2019 Phage display of the human proteome identified 29 validated LC8-binding peptides (19 entirely novel), all containing the canonical TQT motif anchor. Residues outside the TQT anchor critically determine binding: numerous TQT-containing peptides do not bind LC8. The LC8Pred algorithm was developed to predict binding motifs with ~78% accuracy, substantially expanding the scope of the DYNLL1 hub interactome. Proteomic phage display, isothermal titration calorimetry (29 peptides validated), computational motif analysis Life Science Alliance High 31266884
2019 NMR and SAXS showed that LC8 binding to a disordered linker adjacent to the rabies virus phosphoprotein (RavP) endogenous dimerization domain restricts RavP domain orientations. The resulting RavP-LC8 tetrameric ensemble structure resembles that of a related phosphoprotein that does not bind LC8, indicating LC8 induces a more active conformation in RavP. LC8 interactions are essential for efficient viral polymerase functionality and are highly conserved in Lyssavirus phosphoproteins. NMR, SAXS, molecular modeling, colocalization in infected cells, viral polymerase activity assay Journal of Molecular Biology High 31634467
2020 LC8 (DYNLL1) binds predominantly 'in-register' to the multivalent intrinsically disordered ASCIZ transcription activation domain (three LC8-recognition motifs). NMR chemical shift perturbation, analytical ultracentrifugation, and native electrospray ionization MS demonstrated in-register complex formation. At sub-stoichiometric LC8 concentrations, one of the three motifs is preferentially occupied. Linker length between motifs and motif specificity are identified as key drivers of in-register assembly. NMR chemical shift perturbation, saturation transfer difference NMR, analytical ultracentrifugation, native ESI-MS The Journal of Biological Chemistry High 32139510
2021 In Drosophila ovaries, dynein light chain LC8/Cut-up (the ortholog of DYNLL1) is an essential component of the PICTS co-transcriptional transposon silencing complex (containing Panoramix, Nxf2, Nxt1). LC8/Cut-up loss results in transposon de-repression and loss of repressive chromatin marks at transposon loci. LC8/Cut-up drives dimerization of the PICTS complex through binding conserved motifs in Panoramix; artificial dimerization of Panoramix bypasses the requirement for LC8/Cut-up, demonstrating that LC8's dimerization function is the essential mechanistic contribution. Genetic knockout, transposon expression assays, ChIP-seq, RNA-seq, artificial dimerization rescue, Co-immunoprecipitation eLife High 33538693
2023 DYNLL1 is recruited to DNA double-strand breaks by 53BP1 where it limits end resection by binding and disrupting the MRE11 dimer. The Shieldin complex is recruited to a fraction of 53BP1-positive DSBs hours after DYNLL1, predominantly in G1 cells, and its localization depends on MRE11 activity and is regulated by the DYNLL1–MRE11 interaction. BRCA1-deficient cells rendered resistant to PARP inhibitors by Shieldin loss can be resensitized by constitutive DYNLL1–MRE11 association, defining the temporal and functional hierarchy of the 53BP1-centric anti-resection machinery. Live-cell imaging, proximity ligation assay, Co-IP, genetic knockouts, PARP inhibitor sensitivity assays, cell-cycle-specific analyses Nature Structural & Molecular Biology High 37696958

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Network organization of the human autophagy system. Nature 1286 20562859
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2003 JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America 881 12591950
1999 The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Molecular cell 873 10198631
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2015 PIN-dependent auxin transport: action, regulation, and evolution. The Plant cell 555 25604445
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2011 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 507 21565611
2005 Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proceedings of the National Academy of Sciences of the United States of America 497 15937109
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
1995 Cell cycle regulation of the activity and subcellular localization of Plk1, a human protein kinase implicated in mitotic spindle function. The Journal of cell biology 427 7790358
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2010 The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. The Journal of cell biology 395 20921139
1996 PIN: an associated protein inhibitor of neuronal nitric oxide synthase. Science (New York, N.Y.) 393 8864115
2013 Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Science signaling 383 24255178
2000 A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function. Nature cell biology 368 11056532
2018 SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature 360 29670289
2009 The PIN-FORMED (PIN) protein family of auxin transporters. Genome biology 349 20053306
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2018 DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Nature 188 30464262
2007 DLC-1:a Rho GTPase-activating protein and tumour suppressor. Journal of cellular and molecular medicine 162 17979893
2009 PIN phosphorylation is sufficient to mediate PIN polarity and direct auxin transport. Proceedings of the National Academy of Sciences of the United States of America 161 20080776
2008 DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma. Genes & development 160 18519636
2000 Dependence and independence of [PSI(+)] and [PIN(+)]: a two-prion system in yeast? The EMBO journal 160 10790361
2010 The PIN-domain ribonucleases and the prokaryotic VapBC toxin-antitoxin array. Protein engineering, design & selection : PEDS 152 21036780
1999 Structure of the PIN/LC8 dimer with a bound peptide. Nature structural biology 142 10426949
2009 Subcellular trafficking of PIN auxin efflux carriers in auxin transport. European journal of cell biology 136 19944476
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