{"gene":"DYNLL2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2011,"finding":"DYNLL1 and DYNLL2 (LC8 family) function as regulatory hub proteins that interact with short linear motifs (KXTQT and XG(I/V)QVD) in intrinsically disordered segments of binding partners, promoting dimerization of those partners rather than acting as simple cargo adaptors for dynein/myosin motors. Binding partners include the dynein intermediate chain, myosin 5a, and diverse scaffold proteins.","method":"Review synthesizing structural and functional studies; yeast two-hybrid, peptide binding, co-IP, structural data from multiple labs","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods across many labs, independently replicated; review consolidates structural and functional evidence","pmids":["21777386"],"is_preprint":false},{"year":2010,"finding":"DYNLL2 binds two putative consensus motifs (KXTQTX and XG(I/V)QVD) with micromolar affinity, with the KXTQTX motif showing slower off-rate constants. Binding kinetics best fit a conformational selection model (slow isomerization + rapid binding). A phosphomimetic S88E mutant of DYNLL2 shows significantly lower apparent Kd for dimeric myosin Va, suggesting phosphorylation modulates binding affinity. Bivalent (dimeric) ligands show strong avidity effects (nanomolar Kd).","method":"In vitro binding assays (isothermal titration calorimetry, surface plasmon resonance), site-directed mutagenesis of DYNLL2 (S88E), comparison of both DYNLL1 and DYNLL2 isoforms","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, thermodynamic and kinetic analysis, single lab with multiple orthogonal methods","pmids":["20889982"],"is_preprint":false},{"year":2014,"finding":"DYNLL2 binds to an extended linear motif in the intrinsically disordered tail of myosin 5a. In the free form the motif has nascent helical character; upon DYNLL2 binding it folds into a β-strand occupying each of the two parallel binding grooves of the DYNLL2 homodimer. Flanking residues make additional contacts: the N-terminal extension folds back to partially block the free β-sheet edge, and the C-terminal extension contacts the dimer interface and interacts with the symmetry-related second myosin 5a peptide.","method":"NMR spectroscopy, X-ray crystallography, molecular dynamics simulations","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure + NMR + MD in a single study with multiple orthogonal methods","pmids":["25312846"],"is_preprint":false},{"year":2014,"finding":"DYNLL1 and DYNLL2 are subunits of the human cytoplasmic dynein-2 complex, which mediates retrograde intraflagellar transport (IFT). They associate with the dynein-2 intermediate chain WDR34. The dynein-2 complex composition was defined to include DYNLL1/DYNLL2 as shared subunits.","method":"Co-immunoprecipitation/mass spectrometry to define complex composition; siRNA knockdown functional assays for cilia","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP and MS, independently replicated across subsequent studies (PMID 29742051, 30649997)","pmids":["25205765"],"is_preprint":false},{"year":2014,"finding":"DYNLL1 and DYNLL2 localize to cilia in puncta consistent with IFT particles and physically interact with WDR34, a dynein-2 intermediate chain. Expression of DYNLL2 (as well as DYNLL1) rescued ciliogenesis defects caused by ATMIN/DYNLL1 depletion, placing DYNLL2 downstream of ATMIN in ciliogenesis.","method":"Immunofluorescence localization to cilia, co-immunoprecipitation with WDR34, rescue experiments by exogenous DYNLL2 expression in ATMIN-depleted cells","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment + Co-IP + functional rescue, single lab","pmids":["25294941"],"is_preprint":false},{"year":2018,"finding":"DYNLL1 and DYNLL2 associate with the WDR34 intermediate chain subcomplex of dynein-2 (WDR34-DYNLL1/DYNLL2-DYNLRB1/DYNLRB2). This subcomplex is one of three defined subcomplexes in dynein-2.","method":"Visible immunoprecipitation (VIP) assay mapping pairwise and higher-order interactions among dynein-2 subunits","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — VIP assay (direct biochemical interaction mapping), single lab","pmids":["29742051"],"is_preprint":false},{"year":2019,"finding":"The WDR34 intermediate chain interacts with DYNLL1/DYNLL2 and DYNLRB1/DYNLRB2 via distinct sites. These interactions are required for retrograde ciliary protein trafficking; WDR34 constructs lacking the DYNLL-binding N-terminal region act in a dominant-negative manner, inhibiting ciliary biogenesis and retrograde trafficking.","method":"Co-immunoprecipitation, knockout cell lines expressing WDR34 deletion/mutant constructs, dominant-negative analysis, ciliary trafficking assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO rescue with defined mutants, dominant-negative constructs, multiple functional readouts in one rigorous study","pmids":["30649997"],"is_preprint":false},{"year":2012,"finding":"DYNLL2 (DLC2) interacts with the postsynaptic scaffold protein GKAP in dendritic spines. This interaction stabilizes scaffolding protein expression at the postsynaptic density and enhances synaptic NMDA receptor activity. The interaction is favored by sustained synaptic activity.","method":"BRET imaging, immunostaining, electrophysiological recording of NMDA receptor-mediated currents, co-expression of interaction-deficient mutants","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BRET, electrophysiology, and immunostaining in single lab with multiple orthogonal methods","pmids":["22328512"],"is_preprint":false},{"year":2014,"finding":"DYNLL2 (DLC2) dimerization is required for its interaction with GKAP. DLC2-GKAP hetero-oligomeric complexes in dendritic shafts comprise ~2 DLC2 and ~2 GKAP monomers, while in dendritic spines the complexes are much larger (~16 DLC2 and ~13 GKAP monomers). Disruption of the GKAP-DLC2 interaction destabilizes these oligomers, decreases spine-preferential localization of GKAP, and inhibits NMDA receptor activity. DLC2 thus acts as a dimerization engine for GKAP to organize the postsynaptic scaffold.","method":"Two-photon scanning number and brightness (sN&B) fluorescence fluctuation microscopy in living neurons, GKAP-DLC2 interaction-deficient mutants","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — novel quantitative live-imaging method (sN&B) with mutant controls, multiple orthogonal readouts, single lab","pmids":["24938595"],"is_preprint":false},{"year":2019,"finding":"DYNLL1 and DYNLL2 both interact with the BH3-only proteins Bim and Bmf (not exclusively isoform-specific). DYNLL1/2 induces homodimerization of Bim and Bmf and promotes formation of ternary Bim-DYNLL-Bmf complexes in cell-free and cellular systems. DYNLL-induced oligomerization stabilizes Bmf by inhibiting its degradation by the ubiquitin-independent 20S proteasome. A DYNLL-binding-deficient Bmf mutant fails to induce Bim degradation upon overexpression, demonstrating that Bmf-induced Bim degradation is mediated through modulation of Bim-DYNLL association rather than displacement from anti-apoptotic Bcl-2 proteins.","method":"Co-immunoprecipitation in cell-free and cellular systems, proteasome degradation assays, overexpression of DYNLL-binding-deficient mutants, cell death assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — cell-free reconstitution, mutagenesis, and cellular validation with multiple orthogonal methods in one study","pmids":["31189926"],"is_preprint":false},{"year":2011,"finding":"DYNLL1 (but not DYNLL2) is expressed in retinal ganglion cells (RGCs), while DYNLL2 is expressed in glia. DYNLL1 is persistently downregulated in glaucomatous RGCs at all measured timepoints. DYNLL2 is upregulated in glia at 2 weeks after glaucoma induction. These findings indicate non-redundant, cell-type-specific expression patterns for the two isoforms in the retina.","method":"Laser capture microdissection of RGCs and GCL, quantitative PCR, immunostaining, rat chronic glaucoma model","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LCM + qPCR + immunostaining, single lab, direct cell-type localization with disease context","pmids":["21145319"],"is_preprint":false},{"year":2023,"finding":"DYNLL2 interacts with MBNL1 in an RNA-independent manner. In neurons, overexpressed MBNL1 and DYNLL2 co-traffic along axonal processes. MBNL1 knockdown impairs retrograde movement of DYNLL2, and in DM1 model brains with reduced cytoplasmic MBNL1, DYNLL2 and activated pTrkB accumulate in the synaptosomal fraction, indicating impaired DYNLL2-dependent retrograde transport of the BDNF-TrkB signaling complex.","method":"Co-immunoprecipitation (RNA-independent), time-lapse live imaging of MBNL1 and DYNLL2 co-movement, shRNA knockdown, subcellular fractionation, DM1 mouse model and postmortem human tissue analysis","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP (RNA-independence confirmed), live imaging, KD with functional readout, single lab","pmids":["36922901"],"is_preprint":false},{"year":2025,"finding":"DYNLL2 interacts with PAK1 to regulate endocytosis of Gram-negative bacterial outer membrane vesicles (OMVs), facilitating cytosolic LPS release and subsequent Caspase-11 inflammasome activation, thereby triggering pyroptosis (GSDMD cleavage). Depletion of DYNLL2 suppresses OMV internalization, Caspase-11/GSDMD cleavage, and proinflammatory cytokine release. Oroxylin A was identified as an inhibitor of the DYNLL2-PAK1 interaction, blocking Caspase-11-dependent pyroptosis in vitro and improving survival in murine endotoxemia models.","method":"Co-immunoprecipitation (DYNLL2-PAK1 interaction), siRNA/shRNA knockdown of DYNLL2 and PAK1, OMV internalization assays, caspase-11/GSDMD cleavage assays, virtual screening, in vitro pharmacological inhibition, murine endotoxemia model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KD with defined cellular phenotype, in vivo model, single lab","pmids":["41360226"],"is_preprint":false},{"year":2015,"finding":"DYNLL2 levels are regulated by fed/fasted states in oxytocin neurons of the hypothalamic paraventricular nucleus, with higher DYNLL2 expression under fed conditions correlating with increased NMDA receptor-mediated excitatory postsynaptic currents, suggesting DYNLL2 participates in NMDA receptor trafficking to the postsynaptic site under metabolic regulation.","method":"Electrophysiological recording (mEPSC and NMDA-EPSCs), western blot/immunostaining for DYNLL2 in PVN oxytocin neurons, fed vs. fasted paradigm","journal":"Neuropeptides","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlation between DYNLL2 levels and NMDA-EPSCs, no direct mechanistic manipulation of DYNLL2 itself","pmids":["26344333"],"is_preprint":false},{"year":2011,"finding":"DYNLL1 binds to multiple SQ/TQ motifs in the C-terminal domain of ATMIN via KXTQT-type linear motifs. Co-expression of mCherry-DYNLL1 and GFP-ATMIN mutually affects intracellular localization: DYNLL1 presence partly impedes DNA-damage-induced nuclear foci formation by ATMIN. (Note: DYNLL2 is implied to share similar binding capacity but DYNLL1 was the primary focus.)","method":"Yeast two-hybrid screen, pepscan, recombinant expression/gel filtration, NMR-modeled complexes, co-expression fluorescence localization, DNA damage assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — NMR structural modeling + yeast two-hybrid + in vitro binding + cellular co-localization, single lab","pmids":["21971545"],"is_preprint":false}],"current_model":"DYNLL2 is a conserved homodimeric hub protein that functions as a dimerization scaffold by binding short linear motifs (KXTQT, XG(I/V)QVD) in intrinsically disordered regions of diverse partners — including the dynein-2 intermediate chain WDR34 (required for retrograde intraflagellar transport and ciliogenesis), myosin 5a, the postsynaptic scaffold GKAP (organizing NMDA receptor activity in dendritic spines), the BH3-only apoptotic proteins Bim and Bmf (controlling their stability and complex formation), MBNL1 (mediating retrograde BDNF-TrkB axonal transport), and PAK1 (regulating OMV endocytosis and Caspase-11-dependent pyroptosis in sepsis); binding affinity is modulated by phosphorylation (S88) and avidity effects from dimeric ligands, and ligand recognition follows a conformational selection mechanism."},"narrative":{"mechanistic_narrative":"DYNLL2 is a conserved homodimeric hub protein that functions not as a simple motor cargo adaptor but as a dimerization engine, recognizing short linear motifs (KXTQT and XG(I/V)QVD types) in intrinsically disordered segments of structurally diverse partners and templating their dimerization [PMID:21777386, PMID:20889982]. Structural analysis shows that a disordered partner motif with nascent helical character folds into a β-strand occupying each of the two parallel grooves of the DYNLL2 homodimer, with flanking residues contacting the dimer interface and the symmetry-related partner peptide; recognition follows a conformational-selection mechanism, binding affinity is tuned by phosphorylation (the S88E phosphomimetic raises affinity for dimeric myosin Va), and bivalent ligands gain nanomolar avidity [PMID:20889982, PMID:25312846]. Through this activity DYNLL2 is incorporated as a shared subunit of the cytoplasmic dynein-2 complex via the WDR34 intermediate chain, an association required for retrograde intraflagellar transport and ciliogenesis [PMID:25205765, PMID:30649997]. The same dimerization activity organizes other systems: it drives oligomerization of the postsynaptic scaffold GKAP to stabilize the postsynaptic density and enhance NMDA receptor activity [PMID:24938595], induces homo- and hetero-dimerization of the BH3-only proteins Bim and Bmf and stabilizes Bmf against 20S proteasomal degradation to modulate apoptosis [PMID:31189926], and mediates MBNL1-dependent retrograde axonal transport of the BDNF–TrkB signaling complex [PMID:36922901]. DYNLL2 also interacts with PAK1 to promote endocytosis of bacterial outer membrane vesicles, enabling cytosolic LPS sensing and Caspase-11-dependent pyroptosis [PMID:41360226].","teleology":[{"year":2010,"claim":"Established the biophysical logic of DYNLL2 ligand recognition—whether it binds defined motifs and how affinity is regulated—resolving that it engages two consensus motifs by conformational selection and is tuned by phosphorylation and ligand valency.","evidence":"In vitro ITC/SPR binding kinetics with S88E mutagenesis on recombinant DYNLL1/DYNLL2","pmids":["20889982"],"confidence":"High","gaps":["Does S88 phosphorylation occur and regulate binding in cells?","Kinase responsible for S88 not identified"]},{"year":2011,"claim":"Reframed DYNLL1/2 from cargo adaptors to dimerization hubs that act on disordered partner motifs, redefining the conceptual role of the protein family.","evidence":"Review synthesizing structural, peptide-binding, Y2H and co-IP data across labs","pmids":["21777386"],"confidence":"High","gaps":["Review-level synthesis; DYNLL2-specific partner repertoire not exhaustively distinguished from DYNLL1"]},{"year":2012,"claim":"Identified GKAP as a postsynaptic DYNLL2 partner, linking the hub to synaptic scaffolding and NMDA receptor function.","evidence":"BRET imaging, electrophysiology and interaction-deficient mutants in neurons","pmids":["22328512"],"confidence":"Medium","gaps":["Stoichiometry and dimerization requirement not yet resolved at this stage","Direct vs indirect interaction not structurally defined"]},{"year":2014,"claim":"Determined the atomic basis of motif recognition—how a disordered partner peptide is captured—showing it folds into a β-strand across both grooves of the homodimer.","evidence":"NMR, X-ray crystallography and MD on the myosin 5a tail motif bound to DYNLL2","pmids":["25312846"],"confidence":"High","gaps":["Structures of other partner complexes not solved","How flanking-region contacts vary across partners unknown"]},{"year":2014,"claim":"Placed DYNLL2 as a shared subunit of cytoplasmic dynein-2 via WDR34, connecting the hub to retrograde IFT and ciliogenesis.","evidence":"Co-IP/MS complex definition, cilia localization, WDR34 co-IP and rescue of ATMIN-depletion ciliogenesis defects","pmids":["25205765","25294941"],"confidence":"High","gaps":["Whether DYNLL2 dimerizes WDR34 specifically not directly shown","Functional redundancy with DYNLL1 in cilia not separated"]},{"year":2014,"claim":"Demonstrated that DYNLL2 acts as a dimerization engine in a physiological scaffold, quantifying GKAP–DLC2 oligomer composition and showing disruption inhibits NMDA receptor activity.","evidence":"Two-photon sN&B fluorescence fluctuation microscopy with interaction-deficient mutants in living neurons","pmids":["24938595"],"confidence":"High","gaps":["What limits oligomer size in spines vs shafts is unknown","Upstream signals controlling activity-dependent assembly not defined"]},{"year":2019,"claim":"Extended the dimerization-hub role to apoptosis, showing DYNLL2 drives Bim/Bmf oligomerization, stabilizes Bmf against the 20S proteasome, and mediates Bmf-induced Bim degradation.","evidence":"Cell-free and cellular co-IP, proteasome degradation assays, DYNLL-binding-deficient mutants, cell death assays","pmids":["31189926"],"confidence":"High","gaps":["Relative contribution of DYNLL1 vs DYNLL2 to apoptotic regulation not separated","Physiological context where this axis dominates unclear"]},{"year":2018,"claim":"Mapped DYNLL2 to a defined dynein-2 subcomplex architecture, clarifying which intermediate/light chains it co-assembles with.","evidence":"Visible immunoprecipitation (VIP) interaction mapping of dynein-2 subunits","pmids":["29742051"],"confidence":"Medium","gaps":["Quantitative stoichiometry within the subcomplex not established"]},{"year":2019,"claim":"Showed the WDR34 N-terminal DYNLL-binding region is functionally required, since its deletion acts dominant-negatively to block retrograde ciliary trafficking.","evidence":"KO cell lines with WDR34 deletion/mutant constructs, dominant-negative analysis, ciliary trafficking assays","pmids":["30649997"],"confidence":"High","gaps":["Whether DYNLL binding promotes WDR34 dimerization in this context not directly tested"]},{"year":2023,"claim":"Linked DYNLL2 to retrograde neurotrophin signaling, showing an RNA-independent MBNL1 interaction is needed for retrograde axonal transport of the BDNF–TrkB complex, with disease relevance in DM1.","evidence":"RNA-independent co-IP, live imaging of co-movement, shRNA knockdown, fractionation, DM1 mouse and human tissue","pmids":["36922901"],"confidence":"Medium","gaps":["Direct binding motif on MBNL1 not mapped","Mechanistic coupling to dynein motor not shown"]},{"year":2025,"claim":"Implicated DYNLL2 in innate immune signaling, showing a PAK1 interaction drives OMV endocytosis enabling cytosolic LPS sensing and Caspase-11-dependent pyroptosis, with a small-molecule disruptor protective in endotoxemia.","evidence":"Co-IP, siRNA/shRNA knockdown, OMV internalization and Caspase-11/GSDMD cleavage assays, virtual screening, murine endotoxemia model","pmids":["41360226"],"confidence":"Medium","gaps":["Direct binding interface with PAK1 not structurally defined","Whether DYNLL2 dimerizes PAK1 as for other partners untested"]},{"year":null,"claim":"How DYNLL2's single dimerization activity is selectively deployed across ciliary, synaptic, apoptotic, transport and immune contexts—and which roles are unique to DYNLL2 versus shared with DYNLL1—remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Isoform-specific (DYNLL2 vs DYNLL1) partner selectivity not systematically mapped","Cellular regulation of S88 phosphorylation in each context unknown","No structures of most partner complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,8,9]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,6,11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,12]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,8]}],"complexes":["cytoplasmic dynein-2"],"partners":["WDR34","MYO5A","GKAP","BCL2L11","BMF","MBNL1","PAK1","ATMIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96FJ2","full_name":"Dynein light chain 2, cytoplasmic","aliases":["8 kDa dynein light chain b","DLC8b","Dynein light chain LC8-type 2"],"length_aa":89,"mass_kda":10.3,"function":"Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function. Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. May play a role in changing or maintaining the spatial distribution of cytoskeletal structures (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q96FJ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DYNLL2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000264364","cell_line_id":"CID001412","localizations":[{"compartment":"centrosome","grade":3},{"compartment":"nuclear_punctae","grade":3},{"compartment":"cell_contact","grade":2},{"compartment":"cytoplasmic","grade":2},{"compartment":"nucleoplasm","grade":2},{"compartment":"cytoskeleton","grade":1}],"interactors":[{"gene":"DYNLL1","stoichiometry":10.0},{"gene":"ZMYM4","stoichiometry":10.0},{"gene":"FAM117B","stoichiometry":10.0},{"gene":"AMOT","stoichiometry":10.0},{"gene":"GLCCI1","stoichiometry":10.0},{"gene":"GOLGB1","stoichiometry":10.0},{"gene":"STRN3","stoichiometry":10.0},{"gene":"CTTNBP2NL","stoichiometry":10.0},{"gene":"DYNC1LI1","stoichiometry":10.0},{"gene":"UBQLN1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001412","total_profiled":1310},"omim":[{"mim_id":"608942","title":"DYNEIN, LIGHT CHAIN, LC8 TYPE, 2; DYNLL2","url":"https://www.omim.org/entry/608942"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Uncertain"},{"location":"Mid piece","reliability":"Uncertain"},{"location":"Principal piece","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DYNLL2"},"hgnc":{"alias_symbol":["MGC17810","Dlc2","DNCL1B","RSPH22"],"prev_symbol":[]},"alphafold":{"accession":"Q96FJ2","domains":[{"cath_id":"3.30.740.10","chopping":"5-86","consensus_level":"high","plddt":97.292,"start":5,"end":86}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FJ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FJ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FJ2-F1-predicted_aligned_error_v6.png","plddt_mean":95.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DYNLL2","jax_strain_url":"https://www.jax.org/strain/search?query=DYNLL2"},"sequence":{"accession":"Q96FJ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96FJ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96FJ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FJ2"}},"corpus_meta":[{"pmid":"21777386","id":"PMC_21777386","title":"DYNLL/LC8: a light chain subunit of the dynein motor complex and beyond.","date":"2011","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/21777386","citation_count":108,"is_preprint":false},{"pmid":"34987704","id":"PMC_34987704","title":"Role of Calcium Signaling Pathway-Related Gene Regulatory Networks in Ischemic Stroke Based on Multiple WGCNA and Single-Cell Analysis.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34987704","citation_count":89,"is_preprint":false},{"pmid":"25205765","id":"PMC_25205765","title":"Subunit composition of the human cytoplasmic dynein-2 complex.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25205765","citation_count":83,"is_preprint":false},{"pmid":"22832404","id":"PMC_22832404","title":"Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and 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science","url":"https://pubmed.ncbi.nlm.nih.gov/24938595","citation_count":9,"is_preprint":false},{"pmid":"28808087","id":"PMC_28808087","title":"The Drosophila LC8 homolog cut up specifies the axonal transport of proteasomes.","date":"2017","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/28808087","citation_count":8,"is_preprint":false},{"pmid":"38454689","id":"PMC_38454689","title":"Aggrephagy-related gene signature correlates with survival and tumor-associated macrophages in glioma: Insights from single-cell and bulk RNA sequencing.","date":"2024","source":"Mathematical biosciences and engineering : MBE","url":"https://pubmed.ncbi.nlm.nih.gov/38454689","citation_count":7,"is_preprint":false},{"pmid":"21145319","id":"PMC_21145319","title":"The expression of dynein light chain DYNLL1 (LC8-1) is persistently downregulated in glaucomatous rat retinal ganglion cells.","date":"2010","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/21145319","citation_count":7,"is_preprint":false},{"pmid":"37283758","id":"PMC_37283758","title":"Machine learning and integrative analysis identify the common pathogenesis of azoospermia complicated with COVID-19.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37283758","citation_count":6,"is_preprint":false},{"pmid":"36922901","id":"PMC_36922901","title":"Loss of MBNL1-mediated retrograde BDNF signaling in the myotonic dystrophy brain.","date":"2023","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/36922901","citation_count":3,"is_preprint":false},{"pmid":"30561290","id":"PMC_30561290","title":"Neospora caninum cytoplasmic dynein LC8 light chain 2 (NcDYNLL2) is differentially produced by pathogenically distinct isolates and regulates the host immune response.","date":"2018","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/30561290","citation_count":3,"is_preprint":false},{"pmid":"41360226","id":"PMC_41360226","title":"Targeting the DYNLL2-PAK1 axis inhibits caspase-11-dependent pyroptosis to alleviate sepsis.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41360226","citation_count":2,"is_preprint":false},{"pmid":"38814181","id":"PMC_38814181","title":"Higher expression of TSR2 aggravating hypertension via the PPAR signaling pathway.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38814181","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16909,"output_tokens":4337,"usd":0.057891,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12255,"output_tokens":3673,"usd":0.07655,"stage2_stop_reason":"end_turn"},"total_usd":0.134441,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"DYNLL1 and DYNLL2 (LC8 family) function as regulatory hub proteins that interact with short linear motifs (KXTQT and XG(I/V)QVD) in intrinsically disordered segments of binding partners, promoting dimerization of those partners rather than acting as simple cargo adaptors for dynein/myosin motors. Binding partners include the dynein intermediate chain, myosin 5a, and diverse scaffold proteins.\",\n      \"method\": \"Review synthesizing structural and functional studies; yeast two-hybrid, peptide binding, co-IP, structural data from multiple labs\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods across many labs, independently replicated; review consolidates structural and functional evidence\",\n      \"pmids\": [\"21777386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DYNLL2 binds two putative consensus motifs (KXTQTX and XG(I/V)QVD) with micromolar affinity, with the KXTQTX motif showing slower off-rate constants. Binding kinetics best fit a conformational selection model (slow isomerization + rapid binding). A phosphomimetic S88E mutant of DYNLL2 shows significantly lower apparent Kd for dimeric myosin Va, suggesting phosphorylation modulates binding affinity. Bivalent (dimeric) ligands show strong avidity effects (nanomolar Kd).\",\n      \"method\": \"In vitro binding assays (isothermal titration calorimetry, surface plasmon resonance), site-directed mutagenesis of DYNLL2 (S88E), comparison of both DYNLL1 and DYNLL2 isoforms\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, thermodynamic and kinetic analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20889982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DYNLL2 binds to an extended linear motif in the intrinsically disordered tail of myosin 5a. In the free form the motif has nascent helical character; upon DYNLL2 binding it folds into a β-strand occupying each of the two parallel binding grooves of the DYNLL2 homodimer. Flanking residues make additional contacts: the N-terminal extension folds back to partially block the free β-sheet edge, and the C-terminal extension contacts the dimer interface and interacts with the symmetry-related second myosin 5a peptide.\",\n      \"method\": \"NMR spectroscopy, X-ray crystallography, molecular dynamics simulations\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure + NMR + MD in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"25312846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DYNLL1 and DYNLL2 are subunits of the human cytoplasmic dynein-2 complex, which mediates retrograde intraflagellar transport (IFT). They associate with the dynein-2 intermediate chain WDR34. The dynein-2 complex composition was defined to include DYNLL1/DYNLL2 as shared subunits.\",\n      \"method\": \"Co-immunoprecipitation/mass spectrometry to define complex composition; siRNA knockdown functional assays for cilia\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP and MS, independently replicated across subsequent studies (PMID 29742051, 30649997)\",\n      \"pmids\": [\"25205765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DYNLL1 and DYNLL2 localize to cilia in puncta consistent with IFT particles and physically interact with WDR34, a dynein-2 intermediate chain. Expression of DYNLL2 (as well as DYNLL1) rescued ciliogenesis defects caused by ATMIN/DYNLL1 depletion, placing DYNLL2 downstream of ATMIN in ciliogenesis.\",\n      \"method\": \"Immunofluorescence localization to cilia, co-immunoprecipitation with WDR34, rescue experiments by exogenous DYNLL2 expression in ATMIN-depleted cells\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment + Co-IP + functional rescue, single lab\",\n      \"pmids\": [\"25294941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DYNLL1 and DYNLL2 associate with the WDR34 intermediate chain subcomplex of dynein-2 (WDR34-DYNLL1/DYNLL2-DYNLRB1/DYNLRB2). This subcomplex is one of three defined subcomplexes in dynein-2.\",\n      \"method\": \"Visible immunoprecipitation (VIP) assay mapping pairwise and higher-order interactions among dynein-2 subunits\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — VIP assay (direct biochemical interaction mapping), single lab\",\n      \"pmids\": [\"29742051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The WDR34 intermediate chain interacts with DYNLL1/DYNLL2 and DYNLRB1/DYNLRB2 via distinct sites. These interactions are required for retrograde ciliary protein trafficking; WDR34 constructs lacking the DYNLL-binding N-terminal region act in a dominant-negative manner, inhibiting ciliary biogenesis and retrograde trafficking.\",\n      \"method\": \"Co-immunoprecipitation, knockout cell lines expressing WDR34 deletion/mutant constructs, dominant-negative analysis, ciliary trafficking assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO rescue with defined mutants, dominant-negative constructs, multiple functional readouts in one rigorous study\",\n      \"pmids\": [\"30649997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DYNLL2 (DLC2) interacts with the postsynaptic scaffold protein GKAP in dendritic spines. This interaction stabilizes scaffolding protein expression at the postsynaptic density and enhances synaptic NMDA receptor activity. The interaction is favored by sustained synaptic activity.\",\n      \"method\": \"BRET imaging, immunostaining, electrophysiological recording of NMDA receptor-mediated currents, co-expression of interaction-deficient mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BRET, electrophysiology, and immunostaining in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22328512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DYNLL2 (DLC2) dimerization is required for its interaction with GKAP. DLC2-GKAP hetero-oligomeric complexes in dendritic shafts comprise ~2 DLC2 and ~2 GKAP monomers, while in dendritic spines the complexes are much larger (~16 DLC2 and ~13 GKAP monomers). Disruption of the GKAP-DLC2 interaction destabilizes these oligomers, decreases spine-preferential localization of GKAP, and inhibits NMDA receptor activity. DLC2 thus acts as a dimerization engine for GKAP to organize the postsynaptic scaffold.\",\n      \"method\": \"Two-photon scanning number and brightness (sN&B) fluorescence fluctuation microscopy in living neurons, GKAP-DLC2 interaction-deficient mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — novel quantitative live-imaging method (sN&B) with mutant controls, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"24938595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DYNLL1 and DYNLL2 both interact with the BH3-only proteins Bim and Bmf (not exclusively isoform-specific). DYNLL1/2 induces homodimerization of Bim and Bmf and promotes formation of ternary Bim-DYNLL-Bmf complexes in cell-free and cellular systems. DYNLL-induced oligomerization stabilizes Bmf by inhibiting its degradation by the ubiquitin-independent 20S proteasome. A DYNLL-binding-deficient Bmf mutant fails to induce Bim degradation upon overexpression, demonstrating that Bmf-induced Bim degradation is mediated through modulation of Bim-DYNLL association rather than displacement from anti-apoptotic Bcl-2 proteins.\",\n      \"method\": \"Co-immunoprecipitation in cell-free and cellular systems, proteasome degradation assays, overexpression of DYNLL-binding-deficient mutants, cell death assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — cell-free reconstitution, mutagenesis, and cellular validation with multiple orthogonal methods in one study\",\n      \"pmids\": [\"31189926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DYNLL1 (but not DYNLL2) is expressed in retinal ganglion cells (RGCs), while DYNLL2 is expressed in glia. DYNLL1 is persistently downregulated in glaucomatous RGCs at all measured timepoints. DYNLL2 is upregulated in glia at 2 weeks after glaucoma induction. These findings indicate non-redundant, cell-type-specific expression patterns for the two isoforms in the retina.\",\n      \"method\": \"Laser capture microdissection of RGCs and GCL, quantitative PCR, immunostaining, rat chronic glaucoma model\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LCM + qPCR + immunostaining, single lab, direct cell-type localization with disease context\",\n      \"pmids\": [\"21145319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DYNLL2 interacts with MBNL1 in an RNA-independent manner. In neurons, overexpressed MBNL1 and DYNLL2 co-traffic along axonal processes. MBNL1 knockdown impairs retrograde movement of DYNLL2, and in DM1 model brains with reduced cytoplasmic MBNL1, DYNLL2 and activated pTrkB accumulate in the synaptosomal fraction, indicating impaired DYNLL2-dependent retrograde transport of the BDNF-TrkB signaling complex.\",\n      \"method\": \"Co-immunoprecipitation (RNA-independent), time-lapse live imaging of MBNL1 and DYNLL2 co-movement, shRNA knockdown, subcellular fractionation, DM1 mouse model and postmortem human tissue analysis\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP (RNA-independence confirmed), live imaging, KD with functional readout, single lab\",\n      \"pmids\": [\"36922901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DYNLL2 interacts with PAK1 to regulate endocytosis of Gram-negative bacterial outer membrane vesicles (OMVs), facilitating cytosolic LPS release and subsequent Caspase-11 inflammasome activation, thereby triggering pyroptosis (GSDMD cleavage). Depletion of DYNLL2 suppresses OMV internalization, Caspase-11/GSDMD cleavage, and proinflammatory cytokine release. Oroxylin A was identified as an inhibitor of the DYNLL2-PAK1 interaction, blocking Caspase-11-dependent pyroptosis in vitro and improving survival in murine endotoxemia models.\",\n      \"method\": \"Co-immunoprecipitation (DYNLL2-PAK1 interaction), siRNA/shRNA knockdown of DYNLL2 and PAK1, OMV internalization assays, caspase-11/GSDMD cleavage assays, virtual screening, in vitro pharmacological inhibition, murine endotoxemia model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KD with defined cellular phenotype, in vivo model, single lab\",\n      \"pmids\": [\"41360226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DYNLL2 levels are regulated by fed/fasted states in oxytocin neurons of the hypothalamic paraventricular nucleus, with higher DYNLL2 expression under fed conditions correlating with increased NMDA receptor-mediated excitatory postsynaptic currents, suggesting DYNLL2 participates in NMDA receptor trafficking to the postsynaptic site under metabolic regulation.\",\n      \"method\": \"Electrophysiological recording (mEPSC and NMDA-EPSCs), western blot/immunostaining for DYNLL2 in PVN oxytocin neurons, fed vs. fasted paradigm\",\n      \"journal\": \"Neuropeptides\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlation between DYNLL2 levels and NMDA-EPSCs, no direct mechanistic manipulation of DYNLL2 itself\",\n      \"pmids\": [\"26344333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DYNLL1 binds to multiple SQ/TQ motifs in the C-terminal domain of ATMIN via KXTQT-type linear motifs. Co-expression of mCherry-DYNLL1 and GFP-ATMIN mutually affects intracellular localization: DYNLL1 presence partly impedes DNA-damage-induced nuclear foci formation by ATMIN. (Note: DYNLL2 is implied to share similar binding capacity but DYNLL1 was the primary focus.)\",\n      \"method\": \"Yeast two-hybrid screen, pepscan, recombinant expression/gel filtration, NMR-modeled complexes, co-expression fluorescence localization, DNA damage assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — NMR structural modeling + yeast two-hybrid + in vitro binding + cellular co-localization, single lab\",\n      \"pmids\": [\"21971545\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DYNLL2 is a conserved homodimeric hub protein that functions as a dimerization scaffold by binding short linear motifs (KXTQT, XG(I/V)QVD) in intrinsically disordered regions of diverse partners — including the dynein-2 intermediate chain WDR34 (required for retrograde intraflagellar transport and ciliogenesis), myosin 5a, the postsynaptic scaffold GKAP (organizing NMDA receptor activity in dendritic spines), the BH3-only apoptotic proteins Bim and Bmf (controlling their stability and complex formation), MBNL1 (mediating retrograde BDNF-TrkB axonal transport), and PAK1 (regulating OMV endocytosis and Caspase-11-dependent pyroptosis in sepsis); binding affinity is modulated by phosphorylation (S88) and avidity effects from dimeric ligands, and ligand recognition follows a conformational selection mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DYNLL2 is a conserved homodimeric hub protein that functions not as a simple motor cargo adaptor but as a dimerization engine, recognizing short linear motifs (KXTQT and XG(I/V)QVD types) in intrinsically disordered segments of structurally diverse partners and templating their dimerization [#0, #1]. Structural analysis shows that a disordered partner motif with nascent helical character folds into a \\u03b2-strand occupying each of the two parallel grooves of the DYNLL2 homodimer, with flanking residues contacting the dimer interface and the symmetry-related partner peptide; recognition follows a conformational-selection mechanism, binding affinity is tuned by phosphorylation (the S88E phosphomimetic raises affinity for dimeric myosin Va), and bivalent ligands gain nanomolar avidity [#1, #2]. Through this activity DYNLL2 is incorporated as a shared subunit of the cytoplasmic dynein-2 complex via the WDR34 intermediate chain, an association required for retrograde intraflagellar transport and ciliogenesis [#3, #6]. The same dimerization activity organizes other systems: it drives oligomerization of the postsynaptic scaffold GKAP to stabilize the postsynaptic density and enhance NMDA receptor activity [#8], induces homo- and hetero-dimerization of the BH3-only proteins Bim and Bmf and stabilizes Bmf against 20S proteasomal degradation to modulate apoptosis [#9], and mediates MBNL1-dependent retrograde axonal transport of the BDNF\\u2013TrkB signaling complex [#11]. DYNLL2 also interacts with PAK1 to promote endocytosis of bacterial outer membrane vesicles, enabling cytosolic LPS sensing and Caspase-11-dependent pyroptosis [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the biophysical logic of DYNLL2 ligand recognition\\u2014whether it binds defined motifs and how affinity is regulated\\u2014resolving that it engages two consensus motifs by conformational selection and is tuned by phosphorylation and ligand valency.\",\n      \"evidence\": \"In vitro ITC/SPR binding kinetics with S88E mutagenesis on recombinant DYNLL1/DYNLL2\",\n      \"pmids\": [\"20889982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does S88 phosphorylation occur and regulate binding in cells?\", \"Kinase responsible for S88 not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reframed DYNLL1/2 from cargo adaptors to dimerization hubs that act on disordered partner motifs, redefining the conceptual role of the protein family.\",\n      \"evidence\": \"Review synthesizing structural, peptide-binding, Y2H and co-IP data across labs\",\n      \"pmids\": [\"21777386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Review-level synthesis; DYNLL2-specific partner repertoire not exhaustively distinguished from DYNLL1\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified GKAP as a postsynaptic DYNLL2 partner, linking the hub to synaptic scaffolding and NMDA receptor function.\",\n      \"evidence\": \"BRET imaging, electrophysiology and interaction-deficient mutants in neurons\",\n      \"pmids\": [\"22328512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and dimerization requirement not yet resolved at this stage\", \"Direct vs indirect interaction not structurally defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Determined the atomic basis of motif recognition\\u2014how a disordered partner peptide is captured\\u2014showing it folds into a \\u03b2-strand across both grooves of the homodimer.\",\n      \"evidence\": \"NMR, X-ray crystallography and MD on the myosin 5a tail motif bound to DYNLL2\",\n      \"pmids\": [\"25312846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of other partner complexes not solved\", \"How flanking-region contacts vary across partners unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed DYNLL2 as a shared subunit of cytoplasmic dynein-2 via WDR34, connecting the hub to retrograde IFT and ciliogenesis.\",\n      \"evidence\": \"Co-IP/MS complex definition, cilia localization, WDR34 co-IP and rescue of ATMIN-depletion ciliogenesis defects\",\n      \"pmids\": [\"25205765\", \"25294941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DYNLL2 dimerizes WDR34 specifically not directly shown\", \"Functional redundancy with DYNLL1 in cilia not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that DYNLL2 acts as a dimerization engine in a physiological scaffold, quantifying GKAP\\u2013DLC2 oligomer composition and showing disruption inhibits NMDA receptor activity.\",\n      \"evidence\": \"Two-photon sN&B fluorescence fluctuation microscopy with interaction-deficient mutants in living neurons\",\n      \"pmids\": [\"24938595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What limits oligomer size in spines vs shafts is unknown\", \"Upstream signals controlling activity-dependent assembly not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the dimerization-hub role to apoptosis, showing DYNLL2 drives Bim/Bmf oligomerization, stabilizes Bmf against the 20S proteasome, and mediates Bmf-induced Bim degradation.\",\n      \"evidence\": \"Cell-free and cellular co-IP, proteasome degradation assays, DYNLL-binding-deficient mutants, cell death assays\",\n      \"pmids\": [\"31189926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of DYNLL1 vs DYNLL2 to apoptotic regulation not separated\", \"Physiological context where this axis dominates unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped DYNLL2 to a defined dynein-2 subcomplex architecture, clarifying which intermediate/light chains it co-assembles with.\",\n      \"evidence\": \"Visible immunoprecipitation (VIP) interaction mapping of dynein-2 subunits\",\n      \"pmids\": [\"29742051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative stoichiometry within the subcomplex not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed the WDR34 N-terminal DYNLL-binding region is functionally required, since its deletion acts dominant-negatively to block retrograde ciliary trafficking.\",\n      \"evidence\": \"KO cell lines with WDR34 deletion/mutant constructs, dominant-negative analysis, ciliary trafficking assays\",\n      \"pmids\": [\"30649997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DYNLL binding promotes WDR34 dimerization in this context not directly tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked DYNLL2 to retrograde neurotrophin signaling, showing an RNA-independent MBNL1 interaction is needed for retrograde axonal transport of the BDNF\\u2013TrkB complex, with disease relevance in DM1.\",\n      \"evidence\": \"RNA-independent co-IP, live imaging of co-movement, shRNA knockdown, fractionation, DM1 mouse and human tissue\",\n      \"pmids\": [\"36922901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding motif on MBNL1 not mapped\", \"Mechanistic coupling to dynein motor not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated DYNLL2 in innate immune signaling, showing a PAK1 interaction drives OMV endocytosis enabling cytosolic LPS sensing and Caspase-11-dependent pyroptosis, with a small-molecule disruptor protective in endotoxemia.\",\n      \"evidence\": \"Co-IP, siRNA/shRNA knockdown, OMV internalization and Caspase-11/GSDMD cleavage assays, virtual screening, murine endotoxemia model\",\n      \"pmids\": [\"41360226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface with PAK1 not structurally defined\", \"Whether DYNLL2 dimerizes PAK1 as for other partners untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DYNLL2's single dimerization activity is selectively deployed across ciliary, synaptic, apoptotic, transport and immune contexts\\u2014and which roles are unique to DYNLL2 versus shared with DYNLL1\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Isoform-specific (DYNLL2 vs DYNLL1) partner selectivity not systematically mapped\", \"Cellular regulation of S88 phosphorylation in each context unknown\", \"No structures of most partner complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 6, 11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\"cytoplasmic dynein-2\"],\n    \"partners\": [\"WDR34\", \"MYO5A\", \"GKAP\", \"BCL2L11\", \"BMF\", \"MBNL1\", \"PAK1\", \"ATMIN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}