{"gene":"GOPC","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2002,"finding":"GOPC is predominantly localized at the trans-Golgi region in round spermatids; GOPC-deficient male mice are infertile with globozoospermia due to fragmentation of acrosomes in early round spermatids — abnormal vesicles fail to fuse to developing acrosomes — establishing GOPC as essential for acrosomal vesicle fusion during spermiogenesis.","method":"Gene knockout mouse (GOPC-deficient), electron microscopy, immunofluorescence, intracytoplasmic sperm injection (ICSI)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotype (acrosome fragmentation), replicated in multiple follow-up studies from independent labs","pmids":["12149515"],"is_preprint":false},{"year":2001,"finding":"GOPC (PIST) directly and specifically binds TC10:GTP (a Rho-family GTPase) via a leucine zipper-containing coiled-coil domain; the first coiled-coil and PDZ domains are not required for TC10 binding, but deletion of the N-terminal portion of the leucine zipper abolishes dimerization. GOPC also forms homodimers.","method":"Yeast two-hybrid, in vitro binding assays, deletion mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding with mutagenesis, single lab, single study","pmids":["11162552"],"is_preprint":false},{"year":2001,"finding":"GOPC interacts with frizzled via the PDZ domain of GOPC and the C-terminal Ser/Thr-X-Val motif of frizzled, both in vivo and in vitro; GOPC and frizzled colocalize at the Golgi apparatus, and coexpression of GOPC with frizzled causes translocation of GOPC to the plasma membrane. Brefeldin A disrupts both GOPC Golgi localization and frizzled plasma membrane targeting, indicating GOPC participates in vesicle transport of frizzled from Golgi to plasma membrane.","method":"Co-immunoprecipitation, in vitro binding, immunofluorescence, deletion mutagenesis, brefeldin A treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus in vitro binding and brefeldin A pharmacological validation, single lab","pmids":["11520064"],"is_preprint":false},{"year":2005,"finding":"GOPC (PIST) interacts with somatostatin receptor subtype 5 (SSTR5) via the PDZ ligand motif at the receptor's C-terminus and retains SSTR5 in the Golgi apparatus when coexpressed. Endogenous SSTR5 in AtT-20 cells colocalizes with PIST in the Golgi. Removal of the PDZ ligand motif inhibits receptor recycling to the plasma membrane after agonist washout, indicating PIST/GOPC is required for postendocytic sorting of SSTR5.","method":"Yeast two-hybrid, coexpression/immunofluorescence, deletion mutagenesis, cell-surface recycling assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus colocalization plus functional recycling assay, single lab","pmids":["16012170"],"is_preprint":false},{"year":2005,"finding":"GOPC (PIST) interacts with golgin-160 via an internal coiled-coil region of PIST and a leucine-rich repeat within golgin-160; they colocalize to Golgi membranes and interact in vivo. A widely expressed isoform, golgin-160B, lacks the leucine repeat and cannot bind PIST.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence colocalization, isoform cloning","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — GST pulldown with defined domain mapping plus co-IP plus colocalization, single lab but multiple orthogonal methods","pmids":["15951434"],"is_preprint":false},{"year":2006,"finding":"GOPC (PIST) PDZ domain solution structure was solved by NMR; it is a canonical class I PDZ domain with two alpha-helices and six beta-strands. Chemical shift perturbation experiments showed the GOPC PDZ domain binds the C-terminal motif of neuroligin in fast exchange with low affinity, and a 3D complex model was constructed by molecular dynamics simulation.","method":"NMR structure determination, chemical shift perturbation, molecular dynamics simulation","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with binding validation by chemical shift perturbation, single lab but rigorous structural method","pmids":["16882988"],"is_preprint":false},{"year":2006,"finding":"GOPC (PIST) binds Rhotekin via its PDZ domain interacting with the C-terminal SPV motif of Rhotekin; this interaction occurs in vitro and in MDCK cells. Activated Rho markedly inhibits the Rhotekin-PIST interaction. PIST and Rhotekin colocalize at the Golgi in non-polarized cells and at adherens junctions in polarized cells, and PIST is involved in recruiting Rhotekin to adherens junctions.","method":"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, immunofluorescence, dominant-active Rho expression","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus in vitro binding plus colocalization plus functional perturbation, single lab","pmids":["16646955"],"is_preprint":false},{"year":2010,"finding":"GOPC (PIST) binds cadherin 23 (CDH23) via the PIST PDZ domain and the C-terminal PDZ domain-binding interface of CDH23, retaining CDH23 in the trans-Golgi network. Co-expression of MAGI-1 or harmonin releases CDH23 from PIST retention, suggesting competitive displacement.","method":"Co-immunoprecipitation, immunofluorescence colocalization, TGN retention assay, competitive coexpression","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus TGN retention assay plus competitive release, single lab","pmids":["20958966"],"is_preprint":false},{"year":2011,"finding":"GOPC PDZ domain binds the C-terminal PDZ motif of transmembrane mucin MUC3. GOPC overexpression downregulates total MUC3 levels, and this effect is reversed by co-introduction of CFTR, indicating CFTR and MUC3 compete for GOPC binding. GOPC also directs CFTR for degradation.","method":"PDZ domain binding screen (123 PDZ domains), co-immunoprecipitation, overexpression with protein level assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic PDZ screen plus functional competition assay, single lab","pmids":["21852426"],"is_preprint":false},{"year":2013,"finding":"GOPC (PIST) mediates a PDZ domain-dependent interaction with the voltage-gated potassium channel KV10.1, enhancing KV10.1 surface levels. The functional (but not physical) interaction requires both coiled-coil and PDZ domains of PIST. The neural isoform nPIST interacts physically but does not alter KV10.1 surface expression. A short isoform sPIST lacks PDZ domain, does not co-precipitate with KV10.1, but reduces KV10.1 surface expression in a dominant-negative manner.","method":"Co-immunoprecipitation from native and expression systems, surface expression assay, isoform cloning and expression, domain mutagenesis","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus surface expression assays plus isoform dissection, single lab","pmids":["23966943"],"is_preprint":false},{"year":2013,"finding":"GOPC (PIST) interacts with NaPi-2a (sodium-phosphate transporter) in the trans-Golgi network during retrograde trafficking from the plasma membrane. PIST overexpression retains NaPi-2a in the TGN and inhibits Na-dependent phosphate transport in OK cells, and prevents adaptation to low-phosphate medium.","method":"Co-immunoprecipitation, immunofluorescence, phosphate transport functional assay, overexpression in OK cells","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP plus functional transport assay, single lab","pmids":["23509734"],"is_preprint":false},{"year":2015,"finding":"GOPC (PIST) controls β1-adrenergic receptor (β1AR) trafficking in both anterograde (biosynthetic) and postendocytic pathways. PIST overexpression retains β1AR in the trans-Golgi network and reduces MAPK signaling by agonist; coexpression with PSD-95 releases receptors to the plasma membrane. cAMP pathway activation relocalizes PIST from TGN to SNX1-positive endosomes where it colocalizes with internalized β1AR and protects receptors from lysosomal degradation. β1AR levels are decreased in hippocampi of PIST-deficient mice.","method":"Overexpression/knockdown, immunofluorescence colocalization, MAPK signaling assay, PIST-KO mouse brain analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — overexpression, knockdown, and KO mouse with multiple functional readouts, single lab but multiple orthogonal approaches","pmids":["25614626"],"is_preprint":false},{"year":2015,"finding":"GOPC localizes to the trans-Golgi network (TGN) in MDCK cells, colocalizing with Rab5 and Rab14 but not Rab11. Knockdown of GOPC decreases transepithelial resistance, increases paracellular flux, and reduces lateral claudin-1 labeling and claudin-2 protein levels, indicating GOPC is required for trafficking of tight junction components from the TGN.","method":"Immunofluorescence colocalization, siRNA knockdown, transepithelial resistance measurement, paracellular flux assay, western blot","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple functional readouts (resistance, flux, protein levels), single lab","pmids":["25616555"],"is_preprint":false},{"year":2016,"finding":"GOPC (PIST) interacts with protocadherin 15 (PCDH15) via the PDZ domain of PIST and the C-terminal PDZ domain-binding interface of PCDH15, retaining PCDH15 in the trans-Golgi network and reducing its membrane expression.","method":"Co-immunoprecipitation, immunofluorescence, TGN retention assay","journal":"Neural plasticity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP plus colocalization, single lab, single study","pmids":["27867666"],"is_preprint":false},{"year":2020,"finding":"HSV-1 protein pUL56 directly binds GOPC, stimulates its ubiquitination and proteasomal degradation. pUL56-mediated GOPC degradation alters cell-surface proteome of infected cells, including loss of TLR2 surface expression, which is GOPC-dependent.","method":"Quantitative multiplexed proteomics (TMT), plasma membrane profiling, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding shown, ubiquitination assay, plasma membrane proteomics, multiple orthogonal methods, single lab","pmids":["33027661"],"is_preprint":false},{"year":2020,"finding":"GOPC interacts with the GTPase ARFRP1 at the trans-Golgi network and together they regulate plasma membrane localization of the SNARE protein SNAP25; knockdown of both GOPC and ARFRP1 in Min6 cells reduces SNAP25 plasma membrane localization and enhances its degradation, impairing glucose-stimulated insulin secretion. Overexpression of SNAP25 or GOPC restores insulin secretion in β-cell-specific Arfrp1-KO islets.","method":"Pulldown with mass spectrometry, co-immunoprecipitation, super-resolution microscopy, siRNA knockdown, glucose-stimulated insulin secretion assay, KO mouse","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — pulldown/MS, co-IP, KO mouse, functional rescue assay — multiple orthogonal methods, single lab","pmids":["33359402"],"is_preprint":false},{"year":2021,"finding":"GOPC (Gopc) is required for synaptic targeting of mGluR5 and neuroligin 1 (Nlgn1) in neurons; knockdown in primary cultured neurons and conditional KO mouse both show impaired plasma membrane targeting of mGlu5 and Nlgn1, while NMDA receptors were unaffected. In Gopc KO hippocampus/cortex, mGlu5 targeting to postsynaptic density is reduced, coinciding with alterations in mGluR-dependent synaptic plasticity and deficits in contextual fear conditioning.","method":"shRNA knockdown in primary neurons, conditional KO mouse, immunofluorescence, synaptic fractionation, mGluR-dependent LTD assay, contextual fear conditioning","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus neuronal knockdown plus electrophysiology plus behavioral assay, single lab but multiple orthogonal methods","pmids":["34383253"],"is_preprint":false},{"year":2022,"finding":"GOPC is required for correct basolateral targeting of syndecan-1 in polarized MDCK cells via interaction with syndecan-1's full-length PDZ motif; this sorting is not dependent on transmembrane domain or sphingomyelin content. GOPC overexpression also alters Golgi morphology, suggesting GOPC affects sorting indirectly through effects on Golgi organization.","method":"siRNA knockdown, domain mutagenesis, trafficking/sorting assay in polarized MDCK cells, Golgi morphology imaging","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD plus mutagenesis plus functional sorting assay, single lab","pmids":["35830596"],"is_preprint":false},{"year":2024,"finding":"GOPC (PIST) traffics from the Golgi to parasitophorous vacuoles (PVs) during Leishmania major infection and associates with autophagy regulatory protein Beclin 1 within PVs (but not with LC3). siRNA silencing of PIST increases parasite burden; PIST overexpression restricts L. major infectivity, establishing PIST as a regulator of Leishmania infection via the Beclin 1-PI3KC3 autophagy pathway.","method":"Immunofluorescence colocalization, co-immunoprecipitation, siRNA knockdown, overexpression, parasite burden quantification","journal":"ACS infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus KD/OE with functional readout (parasite burden), single lab","pmids":["38556987"],"is_preprint":false},{"year":2025,"finding":"MC-LR toxin induces proteasomal degradation of GOPC by promoting excessive ubiquitination via dual inhibition of the deubiquitinase UCHL3: MC-LR directly binds the catalytic domain of UCHL3, blocking its interaction with GOPC and inhibiting its enzymatic activity, while also suppressing UCHL3 transcription and destabilizing UCHL3 protein. UCHL3 dysfunction leads to GOPC ubiquitination and destruction, disrupting acrosome biogenesis.","method":"In vitro binding assay (MC-LR to UCHL3 catalytic domain), ubiquitination assays, co-immunoprecipitation, transcription analysis, protein stability assays","journal":"Environmental pollution","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — direct binding assay plus ubiquitination plus co-IP, single lab, single study","pmids":["40784473"],"is_preprint":false},{"year":2025,"finding":"Leishmania GP63 metalloprotease facilitates PIST-Golgin160 complex formation by suppressing caspase-3 activation, thereby preventing Golgin160 cleavage. GP63 recruits PIST to parasitophorous vacuoles and promotes PIST-Beclin1 colocalization while excluding LC3.","method":"Co-immunoprecipitation, immunofluorescence, GP63-deficient parasite comparison, caspase inhibitor (Z-VAD-FMK) treatment","journal":"ACS infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus genetic (GP63-KO parasite) plus pharmacological manipulation, single lab","pmids":["41269215"],"is_preprint":false},{"year":2025,"finding":"GOPC-ROS1 fusion enhances the catalytic activity of the ROS1 receptor tyrosine kinase fragment and alters the tyrosine phosphorylation profile in human lymphatic endothelial cells. Impaired phosphorylation of ZO-1 at tyrosine 895, due to decreased colocalization of GOPC-ROS1 with ZO-1, inhibits tight junction formation in lymphatic endothelial cells.","method":"Phosphoproteomic profiling, overexpression of fusion protein, colocalization assay, ZO-1 phosphorylation site mutagenesis/validation","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — phosphoproteomics plus functional assay, but focused on GOPC-ROS1 fusion mechanism, single lab","pmids":["40819798"],"is_preprint":false},{"year":2025,"finding":"Using affinity purification mass spectrometry, SHP2 was identified in direct interaction with GOPC-ROS1 (and other ROS1 fusion oncoproteins) but not with ALK fusion oncoproteins; ROS1 fusions phosphorylate SHP2 to a greater extent than ALK fusions, suggesting non-canonical SHP2-driven signaling downstream of GOPC-ROS1.","method":"Affinity purification mass spectrometry, phosphoproteomics","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — AP-MS from a preprint, single lab, no functional validation of GOPC-specific SHP2 interaction beyond proteomic identification","pmids":["bio_10.1101_2025.05.27.656302"],"is_preprint":true},{"year":2013,"finding":"The coiled-coil domain of PIST (amino acids 29-133) was crystallized and X-ray diffraction data collected to 4.0 Å resolution (hexagonal space group P6₂22 or P6₄22); this domain is responsible for interaction with Rab6A and fusion with ROS1.","method":"Protein crystallization, X-ray diffraction","journal":"Acta crystallographica Section F","confidence":"Low","confidence_rationale":"Tier 1 / Weak — preliminary crystallographic study with 4.0 Å resolution only, structure not fully solved, no functional validation in this paper","pmids":["23545662"],"is_preprint":false}],"current_model":"GOPC (PIST/FIG) is a trans-Golgi network-resident scaffolding protein containing PDZ, coiled-coil, and leucine zipper domains that functions as a central regulator of intracellular protein trafficking: it retains diverse plasma membrane cargo (including GPCRs, cadherins, ion channels, transporters, and tight junction proteins) in the TGN via PDZ domain–C-terminal motif interactions, controls their anterograde and postendocytic sorting, and is essential for acrosomal vesicle fusion during spermiogenesis; its activity is regulated by ubiquitination (with UCHL3 as a deubiquitinase), it interacts with ARFRP1 and golgin-160 at the Golgi and with Beclin 1 in autophagic contexts, and it is targeted for proteasomal degradation by HSV-1 pUL56 to remodel the infected cell surface."},"narrative":{"mechanistic_narrative":"GOPC (PIST/FIG) is a trans-Golgi network-resident scaffolding protein that governs the sorting and surface delivery of diverse transmembrane cargo, acting through a modular architecture of PDZ, coiled-coil, and leucine zipper domains [PMID:16882988, PMID:11162552]. Its canonical mode of action is to engage the C-terminal class I PDZ-binding motifs of cargo proteins and thereby retain them in the TGN, modulating whether they reach the plasma membrane; this PDZ-dependent retention has been demonstrated for GPCRs including SSTR5 and β1-adrenergic receptor [PMID:16012170, PMID:25614626], the transmembrane mucin MUC3 [PMID:21852426], the sodium-phosphate transporter NaPi-2a [PMID:23509734], the cadherin-family adhesion proteins CDH23 and PCDH15 [PMID:20958966], and the proteoglycan syndecan-1 [PMID:35830596]. Cargo release from GOPC is controlled by competition from other PDZ proteins (e.g. PSD-95, MAGI-1/harmonin) and by signaling inputs that relocalize GOPC from the TGN to endosomes, where it can protect internalized receptors from lysosomal degradation [PMID:25614626, PMID:20958966]. Beyond retention, GOPC is required for productive anterograde trafficking of several cargoes, partnering with the GTPase ARFRP1 to deliver SNAP25 and support glucose-stimulated insulin secretion [PMID:33359402], directing tight-junction component traffic from the TGN in polarized epithelia [PMID:25616555], and targeting mGluR5 and neuroligin-1 to neuronal synapses where it influences synaptic plasticity and contextual learning [PMID:34383253]. At the organismal level GOPC is essential for acrosomal vesicle fusion during spermiogenesis, and its loss causes globozoospermia and male infertility in mice [PMID:12149515]. GOPC abundance is set by ubiquitin-dependent proteasomal degradation: the deubiquitinase UCHL3 stabilizes GOPC and protects acrosome biogenesis [PMID:40784473], whereas the HSV-1 protein pUL56 binds GOPC and drives its ubiquitination and degradation to remodel the infected-cell surface proteome [PMID:33027661]. GOPC also serves as the N-terminal partner in oncogenic GOPC-ROS1 fusions, contributing a coiled-coil dimerization module that activates the ROS1 kinase domain [PMID:40819798, PMID:23545662].","teleology":[{"year":2001,"claim":"Established the biochemical basis for GOPC's scaffolding behavior by defining its domain-dependent self-association and partner binding, distinguishing the leucine zipper (dimerization, GTPase binding) from the PDZ domain (cargo binding).","evidence":"Yeast two-hybrid, in vitro binding and deletion mutagenesis mapping TC10:GTP binding and homodimerization; reciprocal co-IP and brefeldin A showing PDZ-dependent frizzled binding and Golgi-to-PM transport","pmids":["11162552","11520064"],"confidence":"Medium","gaps":["Physiological consequence of TC10 binding not established","Generality of PDZ-motif cargo recognition not yet shown beyond frizzled at this stage"]},{"year":2002,"claim":"Resolved GOPC's in vivo requirement by showing it is essential for acrosomal vesicle fusion, linking a Golgi scaffold to a defined developmental membrane-fusion event.","evidence":"GOPC-deficient knockout mouse with electron microscopy and immunofluorescence demonstrating acrosome fragmentation and globozoospermia; fertility rescued by ICSI","pmids":["12149515"],"confidence":"High","gaps":["Molecular fusion machinery downstream of GOPC at the acrosome not identified","Whether the spermiogenesis role uses the same PDZ-cargo mechanism as somatic trafficking unknown"]},{"year":2005,"claim":"Generalized the cargo-retention model by showing GOPC retains GPCRs in the Golgi via PDZ-motif binding and controls their postendocytic recycling, and mapped a coiled-coil interaction with the Golgi structural protein golgin-160.","evidence":"Yeast two-hybrid, cell-surface recycling assays for SSTR5; GST pulldown, co-IP and isoform analysis for golgin-160 binding","pmids":["16012170","15951434"],"confidence":"High","gaps":["How the golgin-160 interaction couples to cargo sorting not defined","Recycling mechanism for SSTR5 vs other cargo not compared"]},{"year":2006,"claim":"Provided the structural definition of the GOPC PDZ domain as a canonical class I module and characterized its low-affinity recognition of C-terminal motifs, while adding Rho-regulated recruitment of Rhotekin to junctions.","evidence":"NMR solution structure with chemical shift perturbation against neuroligin peptide and MD modeling; co-IP, in vitro binding and dominant-active Rho perturbation for Rhotekin","pmids":["16882988","16646955"],"confidence":"High","gaps":["Affinity is low, leaving avidity/clustering contributions unresolved","Whether Rho signaling regulates other GOPC-cargo interactions not tested"]},{"year":2013,"claim":"Extended the retention/competition paradigm across structurally diverse cargo classes (ion channels, transporters) and revealed isoform-specific outputs, showing GOPC can either enhance or restrain surface expression depending on cargo and isoform.","evidence":"Co-IP, surface expression and transport assays plus isoform/domain dissection for KV10.1 and NaPi-2a; preliminary crystallization of the coiled-coil (29-133)","pmids":["23966943","23509734","23545662"],"confidence":"Medium","gaps":["Coiled-coil structure only at 4.0 Å, not solved","Mechanistic basis for divergent isoform effects on the same cargo unresolved"]},{"year":2016,"claim":"Consolidated GOPC as a general regulator of plasma-membrane and junctional cargo by demonstrating cargo retention controlled by competitive PDZ displacement and a role in tight-junction component trafficking.","evidence":"Co-IP and TGN-retention assays with competitive coexpression (MAGI-1/harmonin) for CDH23/PCDH15; siRNA knockdown with transepithelial resistance, paracellular flux and claudin assays for tight junctions","pmids":["20958966","27867666","25616555"],"confidence":"Medium","gaps":["PCDH15 evidence rests on a single co-IP/colocalization study","Direct cargo for claudin trafficking not mapped"]},{"year":2021,"claim":"Linked GOPC trafficking activity to physiology in neurons and secretory cells, establishing roles in synaptic receptor targeting, plasticity/behavior, and ARFRP1-dependent SNAP25 delivery for insulin secretion.","evidence":"Conditional KO and shRNA in neurons with synaptic fractionation, LTD and fear conditioning for mGluR5/Nlgn1; pulldown-MS, co-IP, KO mouse and glucose-stimulated insulin secretion rescue for ARFRP1/SNAP25; β1AR trafficking with KO mouse brain analysis","pmids":["34383253","33359402","25614626"],"confidence":"High","gaps":["How signaling (cAMP) triggers GOPC relocalization to endosomes mechanistically unclear","Whether SNAP25 delivery uses PDZ binding or coiled-coil/ARFRP1 route not dissected"]},{"year":2020,"claim":"Defined how GOPC levels are post-translationally controlled, showing that ubiquitin-dependent degradation gates its scaffolding function and that pathogens exploit this to remodel the cell surface.","evidence":"Co-IP, ubiquitination and proteasome-inhibitor assays plus plasma-membrane proteomics for HSV-1 pUL56-driven GOPC degradation; MC-LR-induced GOPC ubiquitination via dual inhibition of UCHL3 with binding, ubiquitination and stability assays","pmids":["33027661","40784473"],"confidence":"High","gaps":["The endogenous E3 ligase for GOPC not identified","MC-LR/UCHL3 axis evidence from a single study"]},{"year":2025,"claim":"Characterized two additional disease-relevant contexts: GOPC as a host factor recruited to Leishmania parasitophorous vacuoles through a Beclin1/Golgin160 axis, and GOPC as the dimerization-providing fusion partner that activates ROS1 kinase signaling.","evidence":"Co-IP, colocalization, GP63-KO parasites and caspase inhibition for the Leishmania/Beclin1 axis; phosphoproteomics, fusion overexpression and ZO-1 phosphosite analysis for GOPC-ROS1; AP-MS identifying SHP2 (preprint)","pmids":["38556987","41269215","40819798","bio_10.1101_2025.05.27.656302"],"confidence":"Medium","gaps":["Direct autophagy mechanism (Beclin1-PI3KC3) downstream of GOPC at PVs not fully resolved","SHP2 interaction with GOPC-ROS1 unvalidated functionally (preprint)"]},{"year":null,"claim":"It remains unresolved how GOPC mechanistically switches between cargo retention and productive anterograde/recycling delivery, and what upstream signals and modifications dictate this choice for a given cargo.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting domain occupancy, competitive displacement, and signaling-driven relocalization","Endogenous E3 ligase and full ubiquitination code for GOPC undefined","Acrosome fusion machinery downstream of GOPC unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,7,8,11,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,10,11]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,2,4,6,12]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,6]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,7,11,15,17]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,11,12,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,18,21]}],"complexes":[],"partners":["GOLGA3","ARFRP1","SNAP25","BECN1","UCHL3","CDH23","ROS1","RTKN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HD26","full_name":"Golgi-associated PDZ and coiled-coil motif-containing protein","aliases":["CFTR-associated ligand","Fused in glioblastoma","PDZ protein interacting specifically with TC10","PIST"],"length_aa":462,"mass_kda":50.5,"function":"Plays a role in intracellular protein trafficking and degradation (PubMed:11707463, PubMed:14570915, PubMed:15358775). May regulate CFTR chloride currents and acid-induced ASIC3 currents by modulating cell surface expression of both channels (By similarity). May also regulate the intracellular trafficking of the ADR1B receptor (PubMed:15358775). May play a role in autophagy (By similarity). Together with MARCHF2 mediates the ubiquitination and lysosomal degradation of CFTR (PubMed:23818989). Overexpression results in CFTR intracellular retention and lysosomaldegradation in the lysosomes (PubMed:11707463, PubMed:14570915)","subcellular_location":"Cytoplasm; Golgi apparatus membrane; Golgi apparatus, trans-Golgi network membrane; Synapse; Postsynaptic density; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/Q9HD26/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GOPC","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/GOPC","total_profiled":1310},"omim":[{"mim_id":"613481","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 62: CCDC62","url":"https://www.omim.org/entry/613481"},{"mim_id":"606845","title":"GOLGI-ASSOCIATED PDZ AND COILED-COIL DOMAINS-CONTAINING PROTEIN; GOPC","url":"https://www.omim.org/entry/606845"},{"mim_id":"605926","title":"PROTEIN INTERACTING WITH C KINASE 1; PICK1","url":"https://www.omim.org/entry/605926"},{"mim_id":"603944","title":"SYNTAXIN 6; STX6","url":"https://www.omim.org/entry/603944"},{"mim_id":"602421","title":"CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CFTR","url":"https://www.omim.org/entry/602421"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Calyx","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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GOPC also forms homodimers.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assays, deletion mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding with mutagenesis, single lab, single study\",\n      \"pmids\": [\"11162552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"GOPC interacts with frizzled via the PDZ domain of GOPC and the C-terminal Ser/Thr-X-Val motif of frizzled, both in vivo and in vitro; GOPC and frizzled colocalize at the Golgi apparatus, and coexpression of GOPC with frizzled causes translocation of GOPC to the plasma membrane. Brefeldin A disrupts both GOPC Golgi localization and frizzled plasma membrane targeting, indicating GOPC participates in vesicle transport of frizzled from Golgi to plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding, immunofluorescence, deletion mutagenesis, brefeldin A treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus in vitro binding and brefeldin A pharmacological validation, single lab\",\n      \"pmids\": [\"11520064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GOPC (PIST) interacts with somatostatin receptor subtype 5 (SSTR5) via the PDZ ligand motif at the receptor's C-terminus and retains SSTR5 in the Golgi apparatus when coexpressed. Endogenous SSTR5 in AtT-20 cells colocalizes with PIST in the Golgi. Removal of the PDZ ligand motif inhibits receptor recycling to the plasma membrane after agonist washout, indicating PIST/GOPC is required for postendocytic sorting of SSTR5.\",\n      \"method\": \"Yeast two-hybrid, coexpression/immunofluorescence, deletion mutagenesis, cell-surface recycling assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus colocalization plus functional recycling assay, single lab\",\n      \"pmids\": [\"16012170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"GOPC (PIST) interacts with golgin-160 via an internal coiled-coil region of PIST and a leucine-rich repeat within golgin-160; they colocalize to Golgi membranes and interact in vivo. A widely expressed isoform, golgin-160B, lacks the leucine repeat and cannot bind PIST.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence colocalization, isoform cloning\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — GST pulldown with defined domain mapping plus co-IP plus colocalization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15951434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GOPC (PIST) PDZ domain solution structure was solved by NMR; it is a canonical class I PDZ domain with two alpha-helices and six beta-strands. Chemical shift perturbation experiments showed the GOPC PDZ domain binds the C-terminal motif of neuroligin in fast exchange with low affinity, and a 3D complex model was constructed by molecular dynamics simulation.\",\n      \"method\": \"NMR structure determination, chemical shift perturbation, molecular dynamics simulation\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with binding validation by chemical shift perturbation, single lab but rigorous structural method\",\n      \"pmids\": [\"16882988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GOPC (PIST) binds Rhotekin via its PDZ domain interacting with the C-terminal SPV motif of Rhotekin; this interaction occurs in vitro and in MDCK cells. Activated Rho markedly inhibits the Rhotekin-PIST interaction. PIST and Rhotekin colocalize at the Golgi in non-polarized cells and at adherens junctions in polarized cells, and PIST is involved in recruiting Rhotekin to adherens junctions.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, immunofluorescence, dominant-active Rho expression\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus in vitro binding plus colocalization plus functional perturbation, single lab\",\n      \"pmids\": [\"16646955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GOPC (PIST) binds cadherin 23 (CDH23) via the PIST PDZ domain and the C-terminal PDZ domain-binding interface of CDH23, retaining CDH23 in the trans-Golgi network. Co-expression of MAGI-1 or harmonin releases CDH23 from PIST retention, suggesting competitive displacement.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, TGN retention assay, competitive coexpression\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus TGN retention assay plus competitive release, single lab\",\n      \"pmids\": [\"20958966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GOPC PDZ domain binds the C-terminal PDZ motif of transmembrane mucin MUC3. GOPC overexpression downregulates total MUC3 levels, and this effect is reversed by co-introduction of CFTR, indicating CFTR and MUC3 compete for GOPC binding. GOPC also directs CFTR for degradation.\",\n      \"method\": \"PDZ domain binding screen (123 PDZ domains), co-immunoprecipitation, overexpression with protein level assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic PDZ screen plus functional competition assay, single lab\",\n      \"pmids\": [\"21852426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GOPC (PIST) mediates a PDZ domain-dependent interaction with the voltage-gated potassium channel KV10.1, enhancing KV10.1 surface levels. The functional (but not physical) interaction requires both coiled-coil and PDZ domains of PIST. The neural isoform nPIST interacts physically but does not alter KV10.1 surface expression. A short isoform sPIST lacks PDZ domain, does not co-precipitate with KV10.1, but reduces KV10.1 surface expression in a dominant-negative manner.\",\n      \"method\": \"Co-immunoprecipitation from native and expression systems, surface expression assay, isoform cloning and expression, domain mutagenesis\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus surface expression assays plus isoform dissection, single lab\",\n      \"pmids\": [\"23966943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GOPC (PIST) interacts with NaPi-2a (sodium-phosphate transporter) in the trans-Golgi network during retrograde trafficking from the plasma membrane. PIST overexpression retains NaPi-2a in the TGN and inhibits Na-dependent phosphate transport in OK cells, and prevents adaptation to low-phosphate medium.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, phosphate transport functional assay, overexpression in OK cells\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP plus functional transport assay, single lab\",\n      \"pmids\": [\"23509734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GOPC (PIST) controls β1-adrenergic receptor (β1AR) trafficking in both anterograde (biosynthetic) and postendocytic pathways. PIST overexpression retains β1AR in the trans-Golgi network and reduces MAPK signaling by agonist; coexpression with PSD-95 releases receptors to the plasma membrane. cAMP pathway activation relocalizes PIST from TGN to SNX1-positive endosomes where it colocalizes with internalized β1AR and protects receptors from lysosomal degradation. β1AR levels are decreased in hippocampi of PIST-deficient mice.\",\n      \"method\": \"Overexpression/knockdown, immunofluorescence colocalization, MAPK signaling assay, PIST-KO mouse brain analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — overexpression, knockdown, and KO mouse with multiple functional readouts, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"25614626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GOPC localizes to the trans-Golgi network (TGN) in MDCK cells, colocalizing with Rab5 and Rab14 but not Rab11. Knockdown of GOPC decreases transepithelial resistance, increases paracellular flux, and reduces lateral claudin-1 labeling and claudin-2 protein levels, indicating GOPC is required for trafficking of tight junction components from the TGN.\",\n      \"method\": \"Immunofluorescence colocalization, siRNA knockdown, transepithelial resistance measurement, paracellular flux assay, western blot\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple functional readouts (resistance, flux, protein levels), single lab\",\n      \"pmids\": [\"25616555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GOPC (PIST) interacts with protocadherin 15 (PCDH15) via the PDZ domain of PIST and the C-terminal PDZ domain-binding interface of PCDH15, retaining PCDH15 in the trans-Golgi network and reducing its membrane expression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, TGN retention assay\",\n      \"journal\": \"Neural plasticity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP plus colocalization, single lab, single study\",\n      \"pmids\": [\"27867666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSV-1 protein pUL56 directly binds GOPC, stimulates its ubiquitination and proteasomal degradation. pUL56-mediated GOPC degradation alters cell-surface proteome of infected cells, including loss of TLR2 surface expression, which is GOPC-dependent.\",\n      \"method\": \"Quantitative multiplexed proteomics (TMT), plasma membrane profiling, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding shown, ubiquitination assay, plasma membrane proteomics, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33027661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GOPC interacts with the GTPase ARFRP1 at the trans-Golgi network and together they regulate plasma membrane localization of the SNARE protein SNAP25; knockdown of both GOPC and ARFRP1 in Min6 cells reduces SNAP25 plasma membrane localization and enhances its degradation, impairing glucose-stimulated insulin secretion. Overexpression of SNAP25 or GOPC restores insulin secretion in β-cell-specific Arfrp1-KO islets.\",\n      \"method\": \"Pulldown with mass spectrometry, co-immunoprecipitation, super-resolution microscopy, siRNA knockdown, glucose-stimulated insulin secretion assay, KO mouse\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — pulldown/MS, co-IP, KO mouse, functional rescue assay — multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33359402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GOPC (Gopc) is required for synaptic targeting of mGluR5 and neuroligin 1 (Nlgn1) in neurons; knockdown in primary cultured neurons and conditional KO mouse both show impaired plasma membrane targeting of mGlu5 and Nlgn1, while NMDA receptors were unaffected. In Gopc KO hippocampus/cortex, mGlu5 targeting to postsynaptic density is reduced, coinciding with alterations in mGluR-dependent synaptic plasticity and deficits in contextual fear conditioning.\",\n      \"method\": \"shRNA knockdown in primary neurons, conditional KO mouse, immunofluorescence, synaptic fractionation, mGluR-dependent LTD assay, contextual fear conditioning\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus neuronal knockdown plus electrophysiology plus behavioral assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34383253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GOPC is required for correct basolateral targeting of syndecan-1 in polarized MDCK cells via interaction with syndecan-1's full-length PDZ motif; this sorting is not dependent on transmembrane domain or sphingomyelin content. GOPC overexpression also alters Golgi morphology, suggesting GOPC affects sorting indirectly through effects on Golgi organization.\",\n      \"method\": \"siRNA knockdown, domain mutagenesis, trafficking/sorting assay in polarized MDCK cells, Golgi morphology imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD plus mutagenesis plus functional sorting assay, single lab\",\n      \"pmids\": [\"35830596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GOPC (PIST) traffics from the Golgi to parasitophorous vacuoles (PVs) during Leishmania major infection and associates with autophagy regulatory protein Beclin 1 within PVs (but not with LC3). siRNA silencing of PIST increases parasite burden; PIST overexpression restricts L. major infectivity, establishing PIST as a regulator of Leishmania infection via the Beclin 1-PI3KC3 autophagy pathway.\",\n      \"method\": \"Immunofluorescence colocalization, co-immunoprecipitation, siRNA knockdown, overexpression, parasite burden quantification\",\n      \"journal\": \"ACS infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus KD/OE with functional readout (parasite burden), single lab\",\n      \"pmids\": [\"38556987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MC-LR toxin induces proteasomal degradation of GOPC by promoting excessive ubiquitination via dual inhibition of the deubiquitinase UCHL3: MC-LR directly binds the catalytic domain of UCHL3, blocking its interaction with GOPC and inhibiting its enzymatic activity, while also suppressing UCHL3 transcription and destabilizing UCHL3 protein. UCHL3 dysfunction leads to GOPC ubiquitination and destruction, disrupting acrosome biogenesis.\",\n      \"method\": \"In vitro binding assay (MC-LR to UCHL3 catalytic domain), ubiquitination assays, co-immunoprecipitation, transcription analysis, protein stability assays\",\n      \"journal\": \"Environmental pollution\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — direct binding assay plus ubiquitination plus co-IP, single lab, single study\",\n      \"pmids\": [\"40784473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Leishmania GP63 metalloprotease facilitates PIST-Golgin160 complex formation by suppressing caspase-3 activation, thereby preventing Golgin160 cleavage. GP63 recruits PIST to parasitophorous vacuoles and promotes PIST-Beclin1 colocalization while excluding LC3.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, GP63-deficient parasite comparison, caspase inhibitor (Z-VAD-FMK) treatment\",\n      \"journal\": \"ACS infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus genetic (GP63-KO parasite) plus pharmacological manipulation, single lab\",\n      \"pmids\": [\"41269215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GOPC-ROS1 fusion enhances the catalytic activity of the ROS1 receptor tyrosine kinase fragment and alters the tyrosine phosphorylation profile in human lymphatic endothelial cells. Impaired phosphorylation of ZO-1 at tyrosine 895, due to decreased colocalization of GOPC-ROS1 with ZO-1, inhibits tight junction formation in lymphatic endothelial cells.\",\n      \"method\": \"Phosphoproteomic profiling, overexpression of fusion protein, colocalization assay, ZO-1 phosphorylation site mutagenesis/validation\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — phosphoproteomics plus functional assay, but focused on GOPC-ROS1 fusion mechanism, single lab\",\n      \"pmids\": [\"40819798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Using affinity purification mass spectrometry, SHP2 was identified in direct interaction with GOPC-ROS1 (and other ROS1 fusion oncoproteins) but not with ALK fusion oncoproteins; ROS1 fusions phosphorylate SHP2 to a greater extent than ALK fusions, suggesting non-canonical SHP2-driven signaling downstream of GOPC-ROS1.\",\n      \"method\": \"Affinity purification mass spectrometry, phosphoproteomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — AP-MS from a preprint, single lab, no functional validation of GOPC-specific SHP2 interaction beyond proteomic identification\",\n      \"pmids\": [\"bio_10.1101_2025.05.27.656302\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The coiled-coil domain of PIST (amino acids 29-133) was crystallized and X-ray diffraction data collected to 4.0 Å resolution (hexagonal space group P6₂22 or P6₄22); this domain is responsible for interaction with Rab6A and fusion with ROS1.\",\n      \"method\": \"Protein crystallization, X-ray diffraction\",\n      \"journal\": \"Acta crystallographica Section F\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — preliminary crystallographic study with 4.0 Å resolution only, structure not fully solved, no functional validation in this paper\",\n      \"pmids\": [\"23545662\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GOPC (PIST/FIG) is a trans-Golgi network-resident scaffolding protein containing PDZ, coiled-coil, and leucine zipper domains that functions as a central regulator of intracellular protein trafficking: it retains diverse plasma membrane cargo (including GPCRs, cadherins, ion channels, transporters, and tight junction proteins) in the TGN via PDZ domain–C-terminal motif interactions, controls their anterograde and postendocytic sorting, and is essential for acrosomal vesicle fusion during spermiogenesis; its activity is regulated by ubiquitination (with UCHL3 as a deubiquitinase), it interacts with ARFRP1 and golgin-160 at the Golgi and with Beclin 1 in autophagic contexts, and it is targeted for proteasomal degradation by HSV-1 pUL56 to remodel the infected cell surface.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GOPC (PIST/FIG) is a trans-Golgi network-resident scaffolding protein that governs the sorting and surface delivery of diverse transmembrane cargo, acting through a modular architecture of PDZ, coiled-coil, and leucine zipper domains [#5, #1]. Its canonical mode of action is to engage the C-terminal class I PDZ-binding motifs of cargo proteins and thereby retain them in the TGN, modulating whether they reach the plasma membrane; this PDZ-dependent retention has been demonstrated for GPCRs including SSTR5 and \\u03b21-adrenergic receptor [#3, #11], the transmembrane mucin MUC3 [#8], the sodium-phosphate transporter NaPi-2a [#10], the cadherin-family adhesion proteins CDH23 and PCDH15 [#7], and the proteoglycan syndecan-1 [#17]. Cargo release from GOPC is controlled by competition from other PDZ proteins (e.g. PSD-95, MAGI-1/harmonin) and by signaling inputs that relocalize GOPC from the TGN to endosomes, where it can protect internalized receptors from lysosomal degradation [#11, #7]. Beyond retention, GOPC is required for productive anterograde trafficking of several cargoes, partnering with the GTPase ARFRP1 to deliver SNAP25 and support glucose-stimulated insulin secretion [#15], directing tight-junction component traffic from the TGN in polarized epithelia [#12], and targeting mGluR5 and neuroligin-1 to neuronal synapses where it influences synaptic plasticity and contextual learning [#16]. At the organismal level GOPC is essential for acrosomal vesicle fusion during spermiogenesis, and its loss causes globozoospermia and male infertility in mice [#0]. GOPC abundance is set by ubiquitin-dependent proteasomal degradation: the deubiquitinase UCHL3 stabilizes GOPC and protects acrosome biogenesis [#19], whereas the HSV-1 protein pUL56 binds GOPC and drives its ubiquitination and degradation to remodel the infected-cell surface proteome [#14]. GOPC also serves as the N-terminal partner in oncogenic GOPC-ROS1 fusions, contributing a coiled-coil dimerization module that activates the ROS1 kinase domain [#21, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the biochemical basis for GOPC's scaffolding behavior by defining its domain-dependent self-association and partner binding, distinguishing the leucine zipper (dimerization, GTPase binding) from the PDZ domain (cargo binding).\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding and deletion mutagenesis mapping TC10:GTP binding and homodimerization; reciprocal co-IP and brefeldin A showing PDZ-dependent frizzled binding and Golgi-to-PM transport\",\n      \"pmids\": [\"11162552\", \"11520064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequence of TC10 binding not established\", \"Generality of PDZ-motif cargo recognition not yet shown beyond frizzled at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved GOPC's in vivo requirement by showing it is essential for acrosomal vesicle fusion, linking a Golgi scaffold to a defined developmental membrane-fusion event.\",\n      \"evidence\": \"GOPC-deficient knockout mouse with electron microscopy and immunofluorescence demonstrating acrosome fragmentation and globozoospermia; fertility rescued by ICSI\",\n      \"pmids\": [\"12149515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular fusion machinery downstream of GOPC at the acrosome not identified\", \"Whether the spermiogenesis role uses the same PDZ-cargo mechanism as somatic trafficking unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Generalized the cargo-retention model by showing GOPC retains GPCRs in the Golgi via PDZ-motif binding and controls their postendocytic recycling, and mapped a coiled-coil interaction with the Golgi structural protein golgin-160.\",\n      \"evidence\": \"Yeast two-hybrid, cell-surface recycling assays for SSTR5; GST pulldown, co-IP and isoform analysis for golgin-160 binding\",\n      \"pmids\": [\"16012170\", \"15951434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the golgin-160 interaction couples to cargo sorting not defined\", \"Recycling mechanism for SSTR5 vs other cargo not compared\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the structural definition of the GOPC PDZ domain as a canonical class I module and characterized its low-affinity recognition of C-terminal motifs, while adding Rho-regulated recruitment of Rhotekin to junctions.\",\n      \"evidence\": \"NMR solution structure with chemical shift perturbation against neuroligin peptide and MD modeling; co-IP, in vitro binding and dominant-active Rho perturbation for Rhotekin\",\n      \"pmids\": [\"16882988\", \"16646955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity is low, leaving avidity/clustering contributions unresolved\", \"Whether Rho signaling regulates other GOPC-cargo interactions not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the retention/competition paradigm across structurally diverse cargo classes (ion channels, transporters) and revealed isoform-specific outputs, showing GOPC can either enhance or restrain surface expression depending on cargo and isoform.\",\n      \"evidence\": \"Co-IP, surface expression and transport assays plus isoform/domain dissection for KV10.1 and NaPi-2a; preliminary crystallization of the coiled-coil (29-133)\",\n      \"pmids\": [\"23966943\", \"23509734\", \"23545662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coiled-coil structure only at 4.0 \\u00c5, not solved\", \"Mechanistic basis for divergent isoform effects on the same cargo unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Consolidated GOPC as a general regulator of plasma-membrane and junctional cargo by demonstrating cargo retention controlled by competitive PDZ displacement and a role in tight-junction component trafficking.\",\n      \"evidence\": \"Co-IP and TGN-retention assays with competitive coexpression (MAGI-1/harmonin) for CDH23/PCDH15; siRNA knockdown with transepithelial resistance, paracellular flux and claudin assays for tight junctions\",\n      \"pmids\": [\"20958966\", \"27867666\", \"25616555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PCDH15 evidence rests on a single co-IP/colocalization study\", \"Direct cargo for claudin trafficking not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked GOPC trafficking activity to physiology in neurons and secretory cells, establishing roles in synaptic receptor targeting, plasticity/behavior, and ARFRP1-dependent SNAP25 delivery for insulin secretion.\",\n      \"evidence\": \"Conditional KO and shRNA in neurons with synaptic fractionation, LTD and fear conditioning for mGluR5/Nlgn1; pulldown-MS, co-IP, KO mouse and glucose-stimulated insulin secretion rescue for ARFRP1/SNAP25; \\u03b21AR trafficking with KO mouse brain analysis\",\n      \"pmids\": [\"34383253\", \"33359402\", \"25614626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How signaling (cAMP) triggers GOPC relocalization to endosomes mechanistically unclear\", \"Whether SNAP25 delivery uses PDZ binding or coiled-coil/ARFRP1 route not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined how GOPC levels are post-translationally controlled, showing that ubiquitin-dependent degradation gates its scaffolding function and that pathogens exploit this to remodel the cell surface.\",\n      \"evidence\": \"Co-IP, ubiquitination and proteasome-inhibitor assays plus plasma-membrane proteomics for HSV-1 pUL56-driven GOPC degradation; MC-LR-induced GOPC ubiquitination via dual inhibition of UCHL3 with binding, ubiquitination and stability assays\",\n      \"pmids\": [\"33027661\", \"40784473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The endogenous E3 ligase for GOPC not identified\", \"MC-LR/UCHL3 axis evidence from a single study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Characterized two additional disease-relevant contexts: GOPC as a host factor recruited to Leishmania parasitophorous vacuoles through a Beclin1/Golgin160 axis, and GOPC as the dimerization-providing fusion partner that activates ROS1 kinase signaling.\",\n      \"evidence\": \"Co-IP, colocalization, GP63-KO parasites and caspase inhibition for the Leishmania/Beclin1 axis; phosphoproteomics, fusion overexpression and ZO-1 phosphosite analysis for GOPC-ROS1; AP-MS identifying SHP2 (preprint)\",\n      \"pmids\": [\"38556987\", \"41269215\", \"40819798\", \"bio_10.1101_2025.05.27.656302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct autophagy mechanism (Beclin1-PI3KC3) downstream of GOPC at PVs not fully resolved\", \"SHP2 interaction with GOPC-ROS1 unvalidated functionally (preprint)\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how GOPC mechanistically switches between cargo retention and productive anterograde/recycling delivery, and what upstream signals and modifications dictate this choice for a given cargo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model connecting domain occupancy, competitive displacement, and signaling-driven relocalization\", \"Endogenous E3 ligase and full ubiquitination code for GOPC undefined\", \"Acrosome fusion machinery downstream of GOPC unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 7, 8, 11, 17]},\n      {\"term_id\": \"GO:0030674\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 2, 4, 6, 12]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 7, 11, 15, 17]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 11, 12, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 18, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"GOLGA3\",\n      \"ARFRP1\",\n      \"SNAP25\",\n      \"BECN1\",\n      \"UCHL3\",\n      \"CDH23\",\n      \"ROS1\",\n      \"RTKN\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}