{"gene":"PACSIN1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2006,"finding":"PACSIN1/syndapin1 directly and selectively binds the carboxy-terminal domain of the NMDAR subunit NR3A through its NPF motifs, assembles a complex including dynamin and clathrin, and mediates activity-dependent endocytosis of NR3A-containing NMDARs from the dendritic plasma membrane; disruption of PACSIN1 function causes NR3A accumulation at synaptic sites.","method":"Co-immunoprecipitation, pulldown assays, dominant-negative disruption in cultured rat hippocampal neurons, live-cell imaging of endocytosis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain-mapping, functional disruption with specific synaptic phenotype, replicated across multiple methods in a focused mechanistic study","pmids":["16617342"],"is_preprint":false},{"year":2017,"finding":"PACSIN1 is the most abundant interactor of the K+-Cl- cotransporter KCC2 in the mouse brain; shRNA knockdown of PACSIN1 in hippocampal neurons increases KCC2 expression and hyperpolarizes the reversal potential for Cl-, establishing PACSIN1 as a negative regulator of KCC2 and thus of synaptic inhibition.","method":"Functional proteomics (native KCC2 interactome by mass spectrometry), biochemical validation of PACSIN1-KCC2 interaction, shRNA knockdown with electrophysiological readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-based interactome, biochemical validation, and functional knockdown with electrophysiological phenotype, multiple orthogonal methods","pmids":["29028184"],"is_preprint":false},{"year":2016,"finding":"PACSIN1 plays dual roles in controlling NMDAR-dependent GluA2 (AMPAR subunit) internalization and recycling; the F-BAR and SH3 domains are required for NMDAR-dependent GluA2 internalization, while the variable region (which binds PICK1) is required for correct AMPAR recycling but not internalization.","method":"pHluorin-GluA2 live-cell imaging, structure-function analysis with domain deletion mutants, NMDAR activation assays in neurons","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis combined with live-cell fluorescent trafficking assay, single lab but multiple orthogonal methods","pmids":["27488904"],"is_preprint":false},{"year":2012,"finding":"PACSIN1 regulates TLR7/9-mediated type I interferon production in plasmacytoid dendritic cells (pDCs); shRNA knockdown in human pDC line inhibits type I IFN response to TLR9 ligand, and PACSIN1-deficient mice show reduced IFN-α production in response to CpG-ODN and virus without affecting proinflammatory cytokine production, indicating a specific role in the type I IFN signaling cascade.","method":"shRNA knockdown in human pDC cell line, PACSIN1 knockout mice, cytokine measurement by ELISA","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in both human cells and knockout mice with specific cytokine readout, single lab","pmids":["22488361"],"is_preprint":false},{"year":2018,"finding":"The SH3 domains of PACSIN1, 2, and 3 bind the proline-rich region (PRR) of the TRPV4 N-terminus as a class I polyproline II helix (with a conserved cis-proline break); PACSIN/Syndapin SH3 domain binding rigidifies both the PRR and the adjacent PIP2 binding site, and PACSIN binding influences the PIP2 binding site but not vice versa, establishing a hierarchical interaction network.","method":"NMR structure determination of PACSIN3 SH3 domain–TRPV4 PRR complex, binding affinity measurements for PACSIN1/2/3 SH3 domains, NMR chemical shift mapping","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with affinity measurements for all three PACSIN paralogs, rigorous structural and biochemical validation in single study","pmids":["30244966"],"is_preprint":false},{"year":2012,"finding":"PACSIN1 interacts with Tau in axons; PACSIN1 blockade impairs axonal elongation and increases primary axonal branching in mouse DRG neurons by increasing Tau binding to microtubules, causing Tau accumulation in the central domain of growth cones and promoting microtubule network stability.","method":"Co-immunoprecipitation, dominant-negative PACSIN1 blockade in mouse DRG neurons, microtubule binding assays, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional loss-of-function with defined cellular phenotype, single lab with multiple methods","pmids":["23035120"],"is_preprint":false},{"year":2021,"finding":"Phosphorylation of Tau at serine residues 396/404 (pTau) decreases Tau:PACSIN1 binding and evokes PACSIN1-dependent functional and structural synapse weakening; knockdown of PACSIN1 increases AMPAR-mediated current at extrasynaptic regions, supporting a role for these proteins in AMPAR trafficking regulation.","method":"In vitro genetic knock-in of phosphorylation mutant human tau in rat CA1 hippocampal neurons, electrophysiology, Co-immunoprecipitation, shRNA knockdown","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphomutant knock-in, electrophysiology, and Co-IP, single lab with multiple orthogonal approaches","pmids":["34290082"],"is_preprint":false},{"year":2022,"finding":"PACSIN1 is required for amphisome-lysosome fusion during basal (nutrient-rich) autophagy but not starvation-induced autophagy; PACSIN1 interacts with the autophagic SNARE protein SNAP29 and is required for proper assembly of STX17 and YKT6 SNARE complexes. PACSIN1 is also required for lysophagy and aggrephagy but not mitophagy, indicating cargo-specific fusion mechanisms.","method":"PACSIN1 deletion, electron microscopy, co-localization analysis, Co-immunoprecipitation with SNAP29/STX17/YKT6, C. elegans sdpn-1 deletion as ortholog validation","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion, electron microscopy, SNARE complex co-IP, cross-species validation in C. elegans, multiple orthogonal methods","pmids":["35771772"],"is_preprint":false},{"year":2023,"finding":"PACSIN1 forms a trimolecular complex with TRAF4 and TRAF6 to regulate type I IFN signaling; the disease-associated Q59K mutation augments PACSIN1 binding to N-WASP while decreasing binding to TRAF4, leading to unrestrained TRAF6-mediated type I IFN activation and selective enhancement of TLR7 (but not TLR9) signaling.","method":"CRISPR/Cas9 introduction of Q59K and null variants, co-immunoprecipitation, luciferase reporter assays, RNA interference, immunofluorescence, flow cytometry","journal":"Arthritis & rheumatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR-edited variants in human cells and mice, Co-IP, reporter assays, and RNAi, multiple orthogonal methods in single study","pmids":["36622335"],"is_preprint":false},{"year":2019,"finding":"Molecular dynamics simulations show that PACSIN1 F-BAR domain has internal structural flexibility and that two PACSIN1 dimers spontaneously assemble via lateral interactions; the assembled dimers bend tensionless lipid membranes, and a single PACSIN1 dimer senses membrane curvature by preferentially binding buckled membranes at a preferred curvature.","method":"All-atom and coarse-grained molecular dynamics simulations of PACSIN1 on lipid membranes","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational simulation only, no experimental validation of the specific membrane bending mechanism","pmids":["31601944"],"is_preprint":false},{"year":2024,"finding":"PACSIN1 released from injured axons binds to the Schwann cell receptor LRP1; recombinant PACSIN1 activates c-Jun and ERK1/2 in Schwann cells in an LRP1-dependent and NMDA-R-dependent manner, and transactivates the receptor tyrosine kinase TrkC to promote Schwann cell repair signaling, migration, and survival.","method":"LRP1-Fc ligand capture from injured nerve, Co-IP validation, recombinant PACSIN1 treatment with LRP1 silencing and TrkC inhibition/silencing, intraneural injection in conditional Lrp1-knockout mice, transcriptome profiling","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ligand capture, Co-IP, conditional knockout mice, pharmacological and genetic inhibition of downstream effectors, multiple orthogonal methods","pmids":["38372375"],"is_preprint":false},{"year":2024,"finding":"PACSIN1 promotes lysosomal fusion and selective autophagy of MHC-I, thereby degrading MHC-I and suppressing antigen presentation and CD8+ T-cell infiltration in gastric cancer; PACSIN1 deficiency inhibits MHC-I autophagy and increases MHC-I surface expression.","method":"PACSIN1 knockout, FISH colocalization of PACSIN1 and MHC-I, flow cytometry for MHC-I and CD8+ T cells, in vivo tumor models","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with colocalization and functional immune readouts, single lab with multiple methods","pmids":["38826133"],"is_preprint":false},{"year":2025,"finding":"UBE3A (the Angelman syndrome E3 ubiquitin ligase) polyubiquitinates PACSIN1 with K48-linked chains to target it for proteasomal degradation; loss of UBE3A increases PACSIN1 protein abundance in human cortical neurons, with implications for AMPA receptor recycling.","method":"LC-MS/MS proteomics of UBE3A knockout vs. wild-type human iPSC-derived cortical neurons, ubiquitination assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS proteomics plus ubiquitination assay, single lab, limited mechanistic follow-up reported in abstract","pmids":["40671377"],"is_preprint":false},{"year":2020,"finding":"NMR backbone and side-chain assignments of the human PACSIN1 SH3 domain identified five β-strands linked by flexible loops, consistent with a canonical SH3 fold, providing structural context for its interaction network.","method":"Solution NMR (2D HSQC/HMQC and multiple 3D experiments), homology modeling","journal":"Biomolecular NMR assignments","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous NMR structural characterization but limited functional validation; single study","pmids":["32236802"],"is_preprint":false}],"current_model":"PACSIN1 is a neuronal F-BAR/SH3 domain adaptor protein that drives membrane curvature and regulates endocytic trafficking; it directly binds NR3A-containing NMDA receptors (via NPF motifs) to mediate their activity-dependent endocytosis, controls AMPA receptor internalization and recycling through its F-BAR and SH3 domains, negatively regulates the K+-Cl- cotransporter KCC2 to modulate synaptic inhibition, binds Tau to regulate microtubule dynamics and axonal growth, facilitates amphisome-lysosome fusion during basal autophagy by organizing STX17/YKT6 SNARE complexes via SNAP29, acts as an axon-derived LRP1 ligand that transactivates TrkC to support Schwann cell repair signaling, forms a TRAF4/TRAF6 trimolecular complex to restrain TLR7-mediated type I interferon production, is itself ubiquitinated by UBE3A for proteasomal degradation, and binds the TRPV4 N-terminal proline-rich region through its SH3 domain to influence channel regulation by PIP2."},"narrative":{"mechanistic_narrative":"PACSIN1 is a neuronal F-BAR/SH3 domain adaptor that couples membrane deformation to the trafficking of synaptic receptors and to membrane fusion events along the autophagic and endocytic pathways [PMID:16617342, PMID:31601944]. At excitatory synapses it directly and selectively binds the NMDAR subunit NR3A through its NPF motifs, assembling a dynamin/clathrin complex that drives activity-dependent endocytosis of NR3A-containing receptors, and its loss causes NR3A to accumulate at synaptic sites [PMID:16617342]. Through distinct modules it also governs AMPA receptor handling, with the F-BAR and SH3 domains required for NMDAR-dependent GluA2 internalization and the PICK1-binding variable region required for AMPAR recycling [PMID:27488904]. PACSIN1 is the most abundant interactor of the K+-Cl- cotransporter KCC2 and acts as a negative regulator of KCC2, tuning synaptic inhibition [PMID:29028184]. Its SH3 domain engages proline-rich ligands including the TRPV4 N-terminal proline-rich region, where binding rigidifies the adjacent PIP2 site in a hierarchical interaction network [PMID:30244966], and it binds Tau in axons to restrain Tau-microtubule association and control axonal elongation and branching [PMID:23035120]. Beyond neurons, PACSIN1 is required for amphisome-lysosome fusion during basal autophagy, where it interacts with the autophagic SNARE SNAP29 and organizes STX17/YKT6 SNARE complex assembly [PMID:35771772], acts as an injured-axon-derived ligand for Schwann-cell LRP1 that transactivates TrkC to support repair signaling [PMID:38372375], and forms a trimolecular complex with TRAF4 and TRAF6 that restrains TLR7-mediated type I interferon production, a balance disrupted by the disease-associated Q59K mutation [PMID:22488361, PMID:36622335]. PACSIN1 protein abundance is itself controlled by UBE3A-mediated K48-linked polyubiquitination targeting it for proteasomal degradation [PMID:40671377].","teleology":[{"year":2006,"claim":"Established PACSIN1 as a receptor-specific endocytic adaptor by showing it directly binds NR3A and drives activity-dependent NMDAR internalization, defining its first mechanistic role at synapses.","evidence":"Co-IP, pulldown, domain mapping and dominant-negative disruption with live imaging in rat hippocampal neurons","pmids":["16617342"],"confidence":"High","gaps":["Does not resolve how NPF-motif binding is regulated by activity","No structural detail of the PACSIN1-dynamin-clathrin assembly"]},{"year":2012,"claim":"Extended PACSIN1 function beyond endocytosis to cytoskeletal regulation by showing it binds Tau and restrains Tau-microtubule association during axon growth.","evidence":"Co-IP, dominant-negative blockade and microtubule binding assays in mouse DRG neurons","pmids":["23035120"],"confidence":"Medium","gaps":["Binding domain on PACSIN1 not mapped","Mechanism by which PACSIN1 limits Tau-MT binding unresolved"]},{"year":2012,"claim":"Identified a non-neuronal role in innate immunity, showing PACSIN1 is selectively required for TLR7/9-driven type I interferon production.","evidence":"shRNA knockdown in human pDC line and PACSIN1 knockout mice with cytokine ELISA","pmids":["22488361"],"confidence":"Medium","gaps":["Molecular partners in the IFN cascade not identified at this stage","Cell-intrinsic mechanism in pDCs unresolved"]},{"year":2016,"claim":"Dissected division of labor among PACSIN1 domains, separating F-BAR/SH3-dependent AMPAR internalization from variable-region/PICK1-dependent recycling.","evidence":"pHluorin-GluA2 live imaging with domain-deletion mutants under NMDAR activation in neurons","pmids":["27488904"],"confidence":"High","gaps":["How the two activities are coordinated temporally unknown","PICK1 binding interface not structurally defined"]},{"year":2017,"claim":"Defined PACSIN1 as a negative regulator of the chloride cotransporter KCC2, linking it to control of synaptic inhibition.","evidence":"Native KCC2 interactome by MS, biochemical validation, shRNA knockdown with electrophysiology","pmids":["29028184"],"confidence":"High","gaps":["Mechanism by which PACSIN1 lowers KCC2 abundance not defined","Direct vs. trafficking-mediated regulation unresolved"]},{"year":2018,"claim":"Provided atomic-level basis for SH3-mediated ligand engagement, showing the SH3 domain binds the TRPV4 proline-rich region and hierarchically rigidifies the adjacent PIP2 site.","evidence":"NMR structure of PACSIN3 SH3-TRPV4 PRR complex with affinity measurements for PACSIN1/2/3","pmids":["30244966"],"confidence":"High","gaps":["Functional consequence for TRPV4 channel gating in cells not measured","PACSIN1-specific contribution vs. paralogs not isolated"]},{"year":2019,"claim":"Modeled how the F-BAR domain senses and bends membranes, proposing lateral dimer assembly and curvature preference.","evidence":"All-atom and coarse-grained molecular dynamics simulations on lipid membranes","pmids":["31601944"],"confidence":"Low","gaps":["Computational only — no experimental validation of the bending mechanism","Predicted curvature preference not tested in cells"]},{"year":2020,"claim":"Provided solution structure of the human PACSIN1 SH3 domain, giving a structural framework for its protein-interaction network.","evidence":"Solution NMR backbone/side-chain assignments and homology modeling","pmids":["32236802"],"confidence":"Medium","gaps":["No ligand-bound structure of PACSIN1 SH3 itself","Limited functional validation"]},{"year":2021,"claim":"Linked Tau phosphorylation to PACSIN1-dependent synapse weakening, connecting the Tau interaction to AMPAR trafficking.","evidence":"Phosphomutant tau knock-in, electrophysiology, Co-IP and shRNA knockdown in rat CA1 neurons","pmids":["34290082"],"confidence":"Medium","gaps":["Mechanism linking reduced Tau:PACSIN1 binding to AMPAR redistribution unclear","Relevance to tauopathy in vivo untested here"]},{"year":2022,"claim":"Established a fusion-machinery role, showing PACSIN1 organizes autophagic SNARE complexes for amphisome-lysosome fusion selectively in basal autophagy.","evidence":"PACSIN1 deletion, EM, colocalization, SNAP29/STX17/YKT6 Co-IP and C. elegans sdpn-1 validation","pmids":["35771772"],"confidence":"High","gaps":["How PACSIN1 distinguishes basal from starvation-induced autophagy unknown","Whether SNARE organization requires membrane bending not resolved"]},{"year":2023,"claim":"Defined the immune mechanism as a TRAF4/TRAF6 trimolecular complex and showed a disease variant (Q59K) shifts binding to unleash TLR7-driven interferon.","evidence":"CRISPR-edited Q59K/null variants in human cells and mice, Co-IP, luciferase reporters, RNAi","pmids":["36622335"],"confidence":"High","gaps":["Structural basis of the TRAF4/TRAF6/PACSIN1 complex not solved","How N-WASP gain-of-binding feeds into TRAF6 activation unresolved"]},{"year":2024,"claim":"Identified PACSIN1 as a secreted axon-derived LRP1 ligand that transactivates TrkC to drive Schwann cell repair, revealing an extracellular signaling role.","evidence":"LRP1-Fc ligand capture, Co-IP, conditional Lrp1-knockout mice, downstream effector inhibition and transcriptomics","pmids":["38372375"],"confidence":"High","gaps":["Mechanism of PACSIN1 release from injured axons unknown","How an F-BAR/SH3 adaptor acts as an extracellular ligand structurally unexplained"]},{"year":2024,"claim":"Connected PACSIN1's autophagy function to immune evasion, showing it promotes selective autophagy of MHC-I and suppresses CD8+ T-cell infiltration in gastric cancer.","evidence":"PACSIN1 knockout, MHC-I/PACSIN1 FISH colocalization, flow cytometry and in vivo tumor models","pmids":["38826133"],"confidence":"Medium","gaps":["Whether MHC-I autophagy uses the same SNAP29/STX17 machinery untested","Direct PACSIN1-MHC-I interaction not demonstrated"]},{"year":2025,"claim":"Placed PACSIN1 under proteostatic control, showing UBE3A K48-polyubiquitinates it for proteasomal degradation, linking it to AMPAR recycling in disease context.","evidence":"LC-MS/MS proteomics of UBE3A-knockout iPSC cortical neurons and ubiquitination assay","pmids":["40671377"],"confidence":"Medium","gaps":["Ubiquitination sites on PACSIN1 not mapped","Functional link to AMPAR recycling not directly tested"]},{"year":null,"claim":"How PACSIN1's membrane-bending F-BAR activity is mechanistically integrated with its diverse SH3-mediated cargo and signaling roles across neurons, autophagy, and immunity remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified structural model linking F-BAR curvature generation to specific cargo selection","Cell-type-specific regulation of the competing interaction network undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[7,11]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,2]}],"complexes":["PACSIN1-TRAF4-TRAF6 complex","STX17/YKT6/SNAP29 autophagic SNARE complex"],"partners":["NR3A","KCC2","TRPV4","TAU","SNAP29","TRAF4","TRAF6","LRP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BY11","full_name":"Protein kinase C and casein kinase substrate in neurons protein 1","aliases":["Syndapin-1"],"length_aa":444,"mass_kda":51.0,"function":"Plays a role in the reorganization of the microtubule cytoskeleton via its interaction with MAPT; this decreases microtubule stability and inhibits MAPT-induced microtubule polymerization. Plays a role in cellular transport processes by recruiting DNM1, DNM2 and DNM3 to membranes. Plays a role in the reorganization of the actin cytoskeleton and in neuron morphogenesis via its interaction with COBL and WASL, and by recruiting COBL to the cell cortex. Plays a role in the regulation of neurite formation, neurite branching and the regulation of neurite length. Required for normal synaptic vesicle endocytosis; this process retrieves previously released neurotransmitters to accommodate multiple cycles of neurotransmission. Required for normal excitatory and inhibitory synaptic transmission (By similarity). Binds to membranes via its F-BAR domain and mediates membrane tubulation","subcellular_location":"Cytoplasm; Cell projection; Synapse, synaptosome; Cell projection, ruffle membrane; Membrane; Cytoplasmic vesicle membrane; Synapse; Cytoplasm, cytosol; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9BY11/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PACSIN1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PACSIN1","total_profiled":1310},"omim":[{"mim_id":"613667","title":"SINE OCULIS-BINDING PROTEIN HOMOLOG; SOBP","url":"https://www.omim.org/entry/613667"},{"mim_id":"606513","title":"PROTEIN KINASE C AND CASEIN KINASE SUBSTRATE IN NEURONS 3; PACSIN3","url":"https://www.omim.org/entry/606513"},{"mim_id":"606512","title":"PROTEIN KINASE C AND CASEIN KINASE SUBSTRATE IN NEURONS 1; PACSIN1","url":"https://www.omim.org/entry/606512"},{"mim_id":"604960","title":"PROTEIN KINASE C AND CASEIN KINASE SUBSTRATE IN NEURONS 2; PACSIN2","url":"https://www.omim.org/entry/604960"},{"mim_id":"143100","title":"HUNTINGTON DISEASE; HD","url":"https://www.omim.org/entry/143100"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":238.9},{"tissue":"retina","ntpm":59.7}],"url":"https://www.proteinatlas.org/search/PACSIN1"},"hgnc":{"alias_symbol":["SDPI"],"prev_symbol":[]},"alphafold":{"accession":"Q9BY11","domains":[{"cath_id":"1.20.1270.60","chopping":"24-259","consensus_level":"medium","plddt":96.8651,"start":24,"end":259},{"cath_id":"2.30.30.40","chopping":"387-442","consensus_level":"high","plddt":91.4148,"start":387,"end":442}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY11","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY11-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY11-F1-predicted_aligned_error_v6.png","plddt_mean":84.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PACSIN1","jax_strain_url":"https://www.jax.org/strain/search?query=PACSIN1"},"sequence":{"accession":"Q9BY11","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BY11.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BY11/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY11"}},"corpus_meta":[{"pmid":"16617342","id":"PMC_16617342","title":"Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1.","date":"2006","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16617342","citation_count":171,"is_preprint":false},{"pmid":"22087336","id":"PMC_22087336","title":"SdPI, the first functionally characterized Kunitz-type trypsin inhibitor from scorpion venom.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22087336","citation_count":57,"is_preprint":false},{"pmid":"29028184","id":"PMC_29028184","title":"Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29028184","citation_count":40,"is_preprint":false},{"pmid":"27488904","id":"PMC_27488904","title":"PACSIN1 regulates the dynamics of AMPA receptor trafficking.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27488904","citation_count":39,"is_preprint":false},{"pmid":"22488361","id":"PMC_22488361","title":"PACSIN1 regulates the TLR7/9-mediated type I interferon response in plasmacytoid dendritic cells.","date":"2012","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22488361","citation_count":37,"is_preprint":false},{"pmid":"30244966","id":"PMC_30244966","title":"Structural Basis of TRPV4 N Terminus Interaction with Syndapin/PACSIN1-3 and PIP2.","date":"2018","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/30244966","citation_count":34,"is_preprint":false},{"pmid":"2426127","id":"PMC_2426127","title":"Evidence for different receptor sites for the novel cardiotonic S-DPI 201-106, ATX II and veratridine on the cardiac sodium channel.","date":"1986","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2426127","citation_count":32,"is_preprint":false},{"pmid":"31601944","id":"PMC_31601944","title":"Curvature induction and sensing of the F-BAR protein Pacsin1 on lipid membranes via molecular dynamics simulations.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31601944","citation_count":31,"is_preprint":false},{"pmid":"23035120","id":"PMC_23035120","title":"PACSIN1, a Tau-interacting protein, regulates axonal elongation and branching by facilitating microtubule instability.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23035120","citation_count":24,"is_preprint":false},{"pmid":"34290082","id":"PMC_34290082","title":"Regulation of Synapse Weakening through Interactions of the Microtubule Associated Protein Tau with PACSIN1.","date":"2021","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34290082","citation_count":20,"is_preprint":false},{"pmid":"35771772","id":"PMC_35771772","title":"PACSIN1 is indispensable for amphisome-lysosome fusion during basal autophagy and subsets of selective autophagy.","date":"2022","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35771772","citation_count":17,"is_preprint":false},{"pmid":"36622335","id":"PMC_36622335","title":"De Novo PACSIN1 Gene Variant Found in Childhood Lupus and a Role for PACSIN1/TRAF4 Complex in Toll-like Receptor 7 Activation.","date":"2023","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/36622335","citation_count":16,"is_preprint":false},{"pmid":"38826133","id":"PMC_38826133","title":"PACSIN1 promotes immunosuppression in gastric cancer by degrading MHC-I.","date":"2024","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/38826133","citation_count":10,"is_preprint":false},{"pmid":"20563570","id":"PMC_20563570","title":"Defense against cannibalism: the SdpI family of bacterial immunity/signal transduction proteins.","date":"2010","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/20563570","citation_count":10,"is_preprint":false},{"pmid":"38372375","id":"PMC_38372375","title":"Axon-derived PACSIN1 binds to the Schwann cell survival receptor, LRP1, and transactivates TrkC to promote gliatrophic activities.","date":"2024","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/38372375","citation_count":4,"is_preprint":false},{"pmid":"40671377","id":"PMC_40671377","title":"The Ubiquitin E3 Ligase UBE3A Regulates GRIPAP1 and PACSIN1 Proteins Linked to the Endocytic Recycling of AMPA Receptors.","date":"2025","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40671377","citation_count":1,"is_preprint":false},{"pmid":"30537176","id":"PMC_30537176","title":"Functional analysis of DNA methylation of the PACSIN1 promoter in pig peripheral blood mononuclear cells.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30537176","citation_count":1,"is_preprint":false},{"pmid":"32236802","id":"PMC_32236802","title":"1H, 13C, and 15N chemical shift assignment of human PACSIN1/syndapin I SH3 domain in solution.","date":"2020","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/32236802","citation_count":1,"is_preprint":false},{"pmid":"40494419","id":"PMC_40494419","title":"ANKK1, ANKRD50, GRK5, PACSIN1 and VPS8 are novel candidate genes associated with late onset Parkinson's disease: Definition of a novel predictive protocol based on polygenic model of inheritance.","date":"2025","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/40494419","citation_count":0,"is_preprint":false},{"pmid":"39923887","id":"PMC_39923887","title":"pacsin1 inhibits antiviral immunity by promoting MITA degradation through autophagy in miiuy croaker, Miichthysmiiuy.","date":"2025","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39923887","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.09.25331163","title":"Proposing a novel Seriously Deteriorated Patient Indicator (SDPI) for hospitalised ward patients","date":"2025-07-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.09.25331163","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11926,"output_tokens":3740,"usd":0.045939,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11409,"output_tokens":4511,"usd":0.08491,"stage2_stop_reason":"end_turn"},"total_usd":0.130849,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"PACSIN1/syndapin1 directly and selectively binds the carboxy-terminal domain of the NMDAR subunit NR3A through its NPF motifs, assembles a complex including dynamin and clathrin, and mediates activity-dependent endocytosis of NR3A-containing NMDARs from the dendritic plasma membrane; disruption of PACSIN1 function causes NR3A accumulation at synaptic sites.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, dominant-negative disruption in cultured rat hippocampal neurons, live-cell imaging of endocytosis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain-mapping, functional disruption with specific synaptic phenotype, replicated across multiple methods in a focused mechanistic study\",\n      \"pmids\": [\"16617342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PACSIN1 is the most abundant interactor of the K+-Cl- cotransporter KCC2 in the mouse brain; shRNA knockdown of PACSIN1 in hippocampal neurons increases KCC2 expression and hyperpolarizes the reversal potential for Cl-, establishing PACSIN1 as a negative regulator of KCC2 and thus of synaptic inhibition.\",\n      \"method\": \"Functional proteomics (native KCC2 interactome by mass spectrometry), biochemical validation of PACSIN1-KCC2 interaction, shRNA knockdown with electrophysiological readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-based interactome, biochemical validation, and functional knockdown with electrophysiological phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29028184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PACSIN1 plays dual roles in controlling NMDAR-dependent GluA2 (AMPAR subunit) internalization and recycling; the F-BAR and SH3 domains are required for NMDAR-dependent GluA2 internalization, while the variable region (which binds PICK1) is required for correct AMPAR recycling but not internalization.\",\n      \"method\": \"pHluorin-GluA2 live-cell imaging, structure-function analysis with domain deletion mutants, NMDAR activation assays in neurons\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis combined with live-cell fluorescent trafficking assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27488904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PACSIN1 regulates TLR7/9-mediated type I interferon production in plasmacytoid dendritic cells (pDCs); shRNA knockdown in human pDC line inhibits type I IFN response to TLR9 ligand, and PACSIN1-deficient mice show reduced IFN-α production in response to CpG-ODN and virus without affecting proinflammatory cytokine production, indicating a specific role in the type I IFN signaling cascade.\",\n      \"method\": \"shRNA knockdown in human pDC cell line, PACSIN1 knockout mice, cytokine measurement by ELISA\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in both human cells and knockout mice with specific cytokine readout, single lab\",\n      \"pmids\": [\"22488361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The SH3 domains of PACSIN1, 2, and 3 bind the proline-rich region (PRR) of the TRPV4 N-terminus as a class I polyproline II helix (with a conserved cis-proline break); PACSIN/Syndapin SH3 domain binding rigidifies both the PRR and the adjacent PIP2 binding site, and PACSIN binding influences the PIP2 binding site but not vice versa, establishing a hierarchical interaction network.\",\n      \"method\": \"NMR structure determination of PACSIN3 SH3 domain–TRPV4 PRR complex, binding affinity measurements for PACSIN1/2/3 SH3 domains, NMR chemical shift mapping\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with affinity measurements for all three PACSIN paralogs, rigorous structural and biochemical validation in single study\",\n      \"pmids\": [\"30244966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PACSIN1 interacts with Tau in axons; PACSIN1 blockade impairs axonal elongation and increases primary axonal branching in mouse DRG neurons by increasing Tau binding to microtubules, causing Tau accumulation in the central domain of growth cones and promoting microtubule network stability.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative PACSIN1 blockade in mouse DRG neurons, microtubule binding assays, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional loss-of-function with defined cellular phenotype, single lab with multiple methods\",\n      \"pmids\": [\"23035120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Phosphorylation of Tau at serine residues 396/404 (pTau) decreases Tau:PACSIN1 binding and evokes PACSIN1-dependent functional and structural synapse weakening; knockdown of PACSIN1 increases AMPAR-mediated current at extrasynaptic regions, supporting a role for these proteins in AMPAR trafficking regulation.\",\n      \"method\": \"In vitro genetic knock-in of phosphorylation mutant human tau in rat CA1 hippocampal neurons, electrophysiology, Co-immunoprecipitation, shRNA knockdown\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphomutant knock-in, electrophysiology, and Co-IP, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"34290082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PACSIN1 is required for amphisome-lysosome fusion during basal (nutrient-rich) autophagy but not starvation-induced autophagy; PACSIN1 interacts with the autophagic SNARE protein SNAP29 and is required for proper assembly of STX17 and YKT6 SNARE complexes. PACSIN1 is also required for lysophagy and aggrephagy but not mitophagy, indicating cargo-specific fusion mechanisms.\",\n      \"method\": \"PACSIN1 deletion, electron microscopy, co-localization analysis, Co-immunoprecipitation with SNAP29/STX17/YKT6, C. elegans sdpn-1 deletion as ortholog validation\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion, electron microscopy, SNARE complex co-IP, cross-species validation in C. elegans, multiple orthogonal methods\",\n      \"pmids\": [\"35771772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PACSIN1 forms a trimolecular complex with TRAF4 and TRAF6 to regulate type I IFN signaling; the disease-associated Q59K mutation augments PACSIN1 binding to N-WASP while decreasing binding to TRAF4, leading to unrestrained TRAF6-mediated type I IFN activation and selective enhancement of TLR7 (but not TLR9) signaling.\",\n      \"method\": \"CRISPR/Cas9 introduction of Q59K and null variants, co-immunoprecipitation, luciferase reporter assays, RNA interference, immunofluorescence, flow cytometry\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR-edited variants in human cells and mice, Co-IP, reporter assays, and RNAi, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36622335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Molecular dynamics simulations show that PACSIN1 F-BAR domain has internal structural flexibility and that two PACSIN1 dimers spontaneously assemble via lateral interactions; the assembled dimers bend tensionless lipid membranes, and a single PACSIN1 dimer senses membrane curvature by preferentially binding buckled membranes at a preferred curvature.\",\n      \"method\": \"All-atom and coarse-grained molecular dynamics simulations of PACSIN1 on lipid membranes\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational simulation only, no experimental validation of the specific membrane bending mechanism\",\n      \"pmids\": [\"31601944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PACSIN1 released from injured axons binds to the Schwann cell receptor LRP1; recombinant PACSIN1 activates c-Jun and ERK1/2 in Schwann cells in an LRP1-dependent and NMDA-R-dependent manner, and transactivates the receptor tyrosine kinase TrkC to promote Schwann cell repair signaling, migration, and survival.\",\n      \"method\": \"LRP1-Fc ligand capture from injured nerve, Co-IP validation, recombinant PACSIN1 treatment with LRP1 silencing and TrkC inhibition/silencing, intraneural injection in conditional Lrp1-knockout mice, transcriptome profiling\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ligand capture, Co-IP, conditional knockout mice, pharmacological and genetic inhibition of downstream effectors, multiple orthogonal methods\",\n      \"pmids\": [\"38372375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PACSIN1 promotes lysosomal fusion and selective autophagy of MHC-I, thereby degrading MHC-I and suppressing antigen presentation and CD8+ T-cell infiltration in gastric cancer; PACSIN1 deficiency inhibits MHC-I autophagy and increases MHC-I surface expression.\",\n      \"method\": \"PACSIN1 knockout, FISH colocalization of PACSIN1 and MHC-I, flow cytometry for MHC-I and CD8+ T cells, in vivo tumor models\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with colocalization and functional immune readouts, single lab with multiple methods\",\n      \"pmids\": [\"38826133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBE3A (the Angelman syndrome E3 ubiquitin ligase) polyubiquitinates PACSIN1 with K48-linked chains to target it for proteasomal degradation; loss of UBE3A increases PACSIN1 protein abundance in human cortical neurons, with implications for AMPA receptor recycling.\",\n      \"method\": \"LC-MS/MS proteomics of UBE3A knockout vs. wild-type human iPSC-derived cortical neurons, ubiquitination assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS proteomics plus ubiquitination assay, single lab, limited mechanistic follow-up reported in abstract\",\n      \"pmids\": [\"40671377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NMR backbone and side-chain assignments of the human PACSIN1 SH3 domain identified five β-strands linked by flexible loops, consistent with a canonical SH3 fold, providing structural context for its interaction network.\",\n      \"method\": \"Solution NMR (2D HSQC/HMQC and multiple 3D experiments), homology modeling\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous NMR structural characterization but limited functional validation; single study\",\n      \"pmids\": [\"32236802\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PACSIN1 is a neuronal F-BAR/SH3 domain adaptor protein that drives membrane curvature and regulates endocytic trafficking; it directly binds NR3A-containing NMDA receptors (via NPF motifs) to mediate their activity-dependent endocytosis, controls AMPA receptor internalization and recycling through its F-BAR and SH3 domains, negatively regulates the K+-Cl- cotransporter KCC2 to modulate synaptic inhibition, binds Tau to regulate microtubule dynamics and axonal growth, facilitates amphisome-lysosome fusion during basal autophagy by organizing STX17/YKT6 SNARE complexes via SNAP29, acts as an axon-derived LRP1 ligand that transactivates TrkC to support Schwann cell repair signaling, forms a TRAF4/TRAF6 trimolecular complex to restrain TLR7-mediated type I interferon production, is itself ubiquitinated by UBE3A for proteasomal degradation, and binds the TRPV4 N-terminal proline-rich region through its SH3 domain to influence channel regulation by PIP2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PACSIN1 is a neuronal F-BAR/SH3 domain adaptor that couples membrane deformation to the trafficking of synaptic receptors and to membrane fusion events along the autophagic and endocytic pathways [#0, #9]. At excitatory synapses it directly and selectively binds the NMDAR subunit NR3A through its NPF motifs, assembling a dynamin/clathrin complex that drives activity-dependent endocytosis of NR3A-containing receptors, and its loss causes NR3A to accumulate at synaptic sites [#0]. Through distinct modules it also governs AMPA receptor handling, with the F-BAR and SH3 domains required for NMDAR-dependent GluA2 internalization and the PICK1-binding variable region required for AMPAR recycling [#2]. PACSIN1 is the most abundant interactor of the K+-Cl- cotransporter KCC2 and acts as a negative regulator of KCC2, tuning synaptic inhibition [#1]. Its SH3 domain engages proline-rich ligands including the TRPV4 N-terminal proline-rich region, where binding rigidifies the adjacent PIP2 site in a hierarchical interaction network [#4], and it binds Tau in axons to restrain Tau-microtubule association and control axonal elongation and branching [#5]. Beyond neurons, PACSIN1 is required for amphisome-lysosome fusion during basal autophagy, where it interacts with the autophagic SNARE SNAP29 and organizes STX17/YKT6 SNARE complex assembly [#7], acts as an injured-axon-derived ligand for Schwann-cell LRP1 that transactivates TrkC to support repair signaling [#10], and forms a trimolecular complex with TRAF4 and TRAF6 that restrains TLR7-mediated type I interferon production, a balance disrupted by the disease-associated Q59K mutation [#3, #8]. PACSIN1 protein abundance is itself controlled by UBE3A-mediated K48-linked polyubiquitination targeting it for proteasomal degradation [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established PACSIN1 as a receptor-specific endocytic adaptor by showing it directly binds NR3A and drives activity-dependent NMDAR internalization, defining its first mechanistic role at synapses.\",\n      \"evidence\": \"Co-IP, pulldown, domain mapping and dominant-negative disruption with live imaging in rat hippocampal neurons\",\n      \"pmids\": [\"16617342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve how NPF-motif binding is regulated by activity\", \"No structural detail of the PACSIN1-dynamin-clathrin assembly\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended PACSIN1 function beyond endocytosis to cytoskeletal regulation by showing it binds Tau and restrains Tau-microtubule association during axon growth.\",\n      \"evidence\": \"Co-IP, dominant-negative blockade and microtubule binding assays in mouse DRG neurons\",\n      \"pmids\": [\"23035120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding domain on PACSIN1 not mapped\", \"Mechanism by which PACSIN1 limits Tau-MT binding unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a non-neuronal role in innate immunity, showing PACSIN1 is selectively required for TLR7/9-driven type I interferon production.\",\n      \"evidence\": \"shRNA knockdown in human pDC line and PACSIN1 knockout mice with cytokine ELISA\",\n      \"pmids\": [\"22488361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners in the IFN cascade not identified at this stage\", \"Cell-intrinsic mechanism in pDCs unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissected division of labor among PACSIN1 domains, separating F-BAR/SH3-dependent AMPAR internalization from variable-region/PICK1-dependent recycling.\",\n      \"evidence\": \"pHluorin-GluA2 live imaging with domain-deletion mutants under NMDAR activation in neurons\",\n      \"pmids\": [\"27488904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the two activities are coordinated temporally unknown\", \"PICK1 binding interface not structurally defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined PACSIN1 as a negative regulator of the chloride cotransporter KCC2, linking it to control of synaptic inhibition.\",\n      \"evidence\": \"Native KCC2 interactome by MS, biochemical validation, shRNA knockdown with electrophysiology\",\n      \"pmids\": [\"29028184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PACSIN1 lowers KCC2 abundance not defined\", \"Direct vs. trafficking-mediated regulation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided atomic-level basis for SH3-mediated ligand engagement, showing the SH3 domain binds the TRPV4 proline-rich region and hierarchically rigidifies the adjacent PIP2 site.\",\n      \"evidence\": \"NMR structure of PACSIN3 SH3-TRPV4 PRR complex with affinity measurements for PACSIN1/2/3\",\n      \"pmids\": [\"30244966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for TRPV4 channel gating in cells not measured\", \"PACSIN1-specific contribution vs. paralogs not isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Modeled how the F-BAR domain senses and bends membranes, proposing lateral dimer assembly and curvature preference.\",\n      \"evidence\": \"All-atom and coarse-grained molecular dynamics simulations on lipid membranes\",\n      \"pmids\": [\"31601944\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational only \\u2014 no experimental validation of the bending mechanism\", \"Predicted curvature preference not tested in cells\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided solution structure of the human PACSIN1 SH3 domain, giving a structural framework for its protein-interaction network.\",\n      \"evidence\": \"Solution NMR backbone/side-chain assignments and homology modeling\",\n      \"pmids\": [\"32236802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand-bound structure of PACSIN1 SH3 itself\", \"Limited functional validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked Tau phosphorylation to PACSIN1-dependent synapse weakening, connecting the Tau interaction to AMPAR trafficking.\",\n      \"evidence\": \"Phosphomutant tau knock-in, electrophysiology, Co-IP and shRNA knockdown in rat CA1 neurons\",\n      \"pmids\": [\"34290082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking reduced Tau:PACSIN1 binding to AMPAR redistribution unclear\", \"Relevance to tauopathy in vivo untested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a fusion-machinery role, showing PACSIN1 organizes autophagic SNARE complexes for amphisome-lysosome fusion selectively in basal autophagy.\",\n      \"evidence\": \"PACSIN1 deletion, EM, colocalization, SNAP29/STX17/YKT6 Co-IP and C. elegans sdpn-1 validation\",\n      \"pmids\": [\"35771772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PACSIN1 distinguishes basal from starvation-induced autophagy unknown\", \"Whether SNARE organization requires membrane bending not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the immune mechanism as a TRAF4/TRAF6 trimolecular complex and showed a disease variant (Q59K) shifts binding to unleash TLR7-driven interferon.\",\n      \"evidence\": \"CRISPR-edited Q59K/null variants in human cells and mice, Co-IP, luciferase reporters, RNAi\",\n      \"pmids\": [\"36622335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the TRAF4/TRAF6/PACSIN1 complex not solved\", \"How N-WASP gain-of-binding feeds into TRAF6 activation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified PACSIN1 as a secreted axon-derived LRP1 ligand that transactivates TrkC to drive Schwann cell repair, revealing an extracellular signaling role.\",\n      \"evidence\": \"LRP1-Fc ligand capture, Co-IP, conditional Lrp1-knockout mice, downstream effector inhibition and transcriptomics\",\n      \"pmids\": [\"38372375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PACSIN1 release from injured axons unknown\", \"How an F-BAR/SH3 adaptor acts as an extracellular ligand structurally unexplained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected PACSIN1's autophagy function to immune evasion, showing it promotes selective autophagy of MHC-I and suppresses CD8+ T-cell infiltration in gastric cancer.\",\n      \"evidence\": \"PACSIN1 knockout, MHC-I/PACSIN1 FISH colocalization, flow cytometry and in vivo tumor models\",\n      \"pmids\": [\"38826133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MHC-I autophagy uses the same SNAP29/STX17 machinery untested\", \"Direct PACSIN1-MHC-I interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed PACSIN1 under proteostatic control, showing UBE3A K48-polyubiquitinates it for proteasomal degradation, linking it to AMPAR recycling in disease context.\",\n      \"evidence\": \"LC-MS/MS proteomics of UBE3A-knockout iPSC cortical neurons and ubiquitination assay\",\n      \"pmids\": [\"40671377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on PACSIN1 not mapped\", \"Functional link to AMPAR recycling not directly tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PACSIN1's membrane-bending F-BAR activity is mechanistically integrated with its diverse SH3-mediated cargo and signaling roles across neurons, autophagy, and immunity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural model linking F-BAR curvature generation to specific cargo selection\", \"Cell-type-specific regulation of the competing interaction network undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\n      \"PACSIN1-TRAF4-TRAF6 complex\",\n      \"STX17/YKT6/SNAP29 autophagic SNARE complex\"\n    ],\n    \"partners\": [\n      \"NR3A\",\n      \"KCC2\",\n      \"TRPV4\",\n      \"Tau\",\n      \"SNAP29\",\n      \"TRAF4\",\n      \"TRAF6\",\n      \"LRP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}