{"gene":"SEC62","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1989,"finding":"SEC62 encodes a membrane protein required for post-translational translocation of secretory precursor proteins into the yeast ER lumen; membranes from sec62 mutant cells display low and labile translocation activity, while cytosol from mutant cells supports normal translocation, demonstrating the defect is membrane-intrinsic.","method":"In vitro translocation assay with membranes/cytosol from mutant and wild-type yeast; DNA sequence analysis predicting two transmembrane domains and cytoplasmic N- and C-terminal domains","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution assay with defined mutant membranes vs. cytosol, replicated across multiple substrates, foundational study","pmids":["2687286"],"is_preprint":false},{"year":2000,"finding":"Mammalian Sec61 exists in ribosome-free complexes associated with Sec62 and Sec63 (homologs of yeast Sec62p/Sec63p), forming a higher-order translocon complex in the ER membrane.","method":"Biochemical fractionation, primary sequence homology analysis, co-isolation of ribosome-free Sec61 complexes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation identifying complex components, single lab, sequence homology corroborating functional assignment","pmids":["10799540"],"is_preprint":false},{"year":2010,"finding":"Human Sec62 has gained an evolutionary function absent in yeast: it interacts with the ribosomal tunnel exit and supports cotranslational protein transport into the ER. Sec62 is associated with ribosomes in human cells and interacts with Sec63.","method":"Ribosome co-sedimentation, co-immunoprecipitation of Sec62 with Sec63 and ribosomes, comparison with yeast ortholog","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and co-sedimentation, single lab, two orthogonal methods","pmids":["20071467"],"is_preprint":false},{"year":2012,"finding":"Silencing SEC62 in human cells specifically inhibits post-translational transport of signal-peptide-containing precursor proteins into the ER, whereas silencing SEC61A1 inhibits both co- and post-translational transport; Sec63 depletion affects the initial phase of co-translational transport.","method":"siRNA knockdown in HeLa cells, in vitro translocation assay with semi-permeabilized cells, substrate-specific analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro translocation assay with defined knockdowns and multiple substrates, clean mechanistic dissection of pathway specificity","pmids":["22375059"],"is_preprint":false},{"year":2012,"finding":"Sec62 is required for efficient post-translational translocation of small proteins (≤100 amino acids) with N-terminal signal sequences in mammalian cells; this Sec62-dependent pathway operates via the Sec61 translocon and requires ATP, functioning as a fail-safe mechanism independent of SRP.","method":"siRNA knockdown of Sec62 and SRP pathway components, in vitro translocation assays, size-class analysis of substrates","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution/translocation assays with defined substrates and ATP requirement tested, multiple substrate classes analyzed","pmids":["22648169"],"is_preprint":false},{"year":2012,"finding":"CK2 phosphorylates Sec63 at serine residues 574, 576, and 748, and this phosphorylation enhances the binding of Sec63 to Sec62, a prerequisite for functional ER protein translocation.","method":"CK2 phosphorylation mapping with deletion mutants and peptide library; pull-down assays and co-immunoprecipitation of Sec63 with Sec62","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical phosphorylation mapping plus reciprocal Co-IP, single lab, two orthogonal methods","pmids":["23287549"],"is_preprint":false},{"year":2013,"finding":"SEC62 (TLOC1) is selectively required for proliferation of cell lines with 3q26 amplification; increased TLOC1 expression induces anchorage-independent growth; TLOC1 binds DDX3X, which is essential for TLOC1-induced cellular transformation.","method":"Loss- and gain-of-function genetic screens, proteomic binding studies identifying DDX3X interaction, anchorage-independent growth assays","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic interaction study plus functional rescue with DDX3X requirement, single lab","pmids":["23764425"],"is_preprint":false},{"year":2013,"finding":"Sec62 directly interacts with the Sec61 complex in a Ca2+-sensitive manner; a Ca2+-binding motif in Sec62 is essential for its molecular function in regulating Ca2+ leakage through Sec61; SEC62 silencing elevates cytosolic Ca2+ and increases ER Ca2+ leakage after thapsigargin treatment.","method":"Biacore surface plasmon resonance (Ca2+-sensitive interaction assay), Ca2+ imaging, siRNA silencing, mutant SEC62 expression","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Biacore direct binding assay plus Ca2+ imaging, single lab, two orthogonal methods","pmids":["24304694"],"is_preprint":false},{"year":2013,"finding":"In yeast, mutations in the N-terminal cytosolic domain of Sec62 impair its interaction with Sec63 and cause defects in membrane insertion and translocation of the C-terminus of membrane proteins, revealing a role for Sec62-Sec63 in topogenesis of membrane proteins.","method":"Yeast mutant analysis, systematic analysis of membrane proteins with varying hydrophobicity and topology, in vivo translocation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutant analysis with multiple substrates, single lab","pmids":["23632075"],"is_preprint":false},{"year":2014,"finding":"The Sec62-Sec63 complex facilitates translocation of the C-terminus of membrane proteins in yeast; mutations in the N-terminal cytosolic domain of Sec62 disrupt Sec62-Sec63 interaction and impair C-terminal translocation of single- and multi-spanning membrane proteins.","method":"Systematic analysis of single and multi-spanning membrane proteins with varying hydrophobicity, flanking charges, and TM orientation in yeast sec62 mutant strains","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic genetic analysis with multiple model substrates, single lab","pmids":["25097231"],"is_preprint":false},{"year":2015,"finding":"Blocking cotranslational translocation by passenger domain folding stabilizes an alternate translocon complex containing Sec61, Sec62, and Sec63; Sec62/63 stabilization within the translocon also occurs for native endogenous substrates (e.g., prion protein) and correlates with a delay in translocation initiation, demonstrating that Sec62/63 engagement is controlled by the nascent chain.","method":"Ribosome-nascent chain isolation, mass spectrometry of translocon complexes, crosslinking, cotranslational translocation assays with preprolactin and prion protein as substrates","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of translocon complexes, MS identification, crosslinking, and functional translocation assays in a single study with multiple substrates","pmids":["25801167"],"is_preprint":false},{"year":2015,"finding":"The SRP receptor (SR) switches the Sec61 translocon from Sec62-dependent to SRP-dependent translocation by displacing Sec62 from Sec61; the charged linker region of SRα mediates this displacement, while a separate conserved element promotes ribosome binding.","method":"Truncation variant analysis of SRα, crosslinking assays, in vitro translocation assays demonstrating Sec62 displacement","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — crosslinking plus translocation assays, single lab, two orthogonal methods","pmids":["26634806"],"is_preprint":false},{"year":2016,"finding":"Sec62 functions as an ER-resident autophagy receptor during recovery from ER stress (recovER-phagy), selectively delivering ER components to autolysosomes; this requires a conserved LC3-interacting region (LIR) in the C-terminal cytosolic domain of Sec62, which is dispensable for protein translocation function.","method":"Autophagy flux assays, LC3-IP, LIR motif mutagenesis, live-cell imaging, fractionation, loss-of-function experiments in mammalian cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — LIR mutagenesis separating ER-phagy from translocation function, LC3 interaction validated biochemically, multiple orthogonal methods, high-impact journal","pmids":["27749824"],"is_preprint":false},{"year":2020,"finding":"Human Sec62/Sec63 substrates share signal peptides with longer but less hydrophobic hydrophobic regions and lower C-region polarity; a slowly gating signal peptide combined with a downstream positively charged amino acid cluster is decisive for Sec62/Sec63 requirement, and these features also correlate with BiP requirement and sensitivity to the Sec61-channel inhibitor CAM741.","method":"Unbiased proteomics approach in intact human cells, siRNA knockdown of SEC62/SEC63, substrate signal peptide analysis of 22 newly identified substrates","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics with defined knockdowns in intact cells, multiple substrates validated, single lab","pmids":["32133789"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of Sec61-Sec62-Sec63 complexes from yeast show that Sec63 and Sec62 stepwise activate Sec61 for post-translational translocation: Sec63 first partially opens the lateral gate via cytosolic and luminal domain interactions with Sec61, then Sec62 is required to displace the plug domain to open the translocation pore; Sec62 may also prevent lipids from entering the channel through the open lateral gate.","method":"Cryo-EM structure determination of multiple complex variants, molecular dynamics simulations, functional mutagenesis analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures at atomic detail combined with MD simulations and mutagenesis, multiple complex variants, high-impact structural biology journal","pmids":["33398175"],"is_preprint":false},{"year":2021,"finding":"Sec62 promotes stemness and chemoresistance of colorectal cancer cells by binding to β-catenin, inhibiting its degradation, and competitively disrupting the interaction between β-catenin and APC, thereby inhibiting β-catenin destruction complex assembly and activating Wnt signaling.","method":"GST pull-down, co-immunoprecipitation, western blot, siRNA knockdown, in vitro and in vivo functional experiments","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pull-down plus reciprocal Co-IP demonstrating direct interaction and APC displacement, single lab","pmids":["33858476"],"is_preprint":false},{"year":2021,"finding":"ATG9A engages SEC62 (and FAM134B) on the cytosolic side of the ER to induce reticulophagy; this engagement depends on the acetylation status of ATG9A in the ER lumen, linking luminal acetylation to cytosolic ER-phagy receptor recruitment.","method":"ATG9A interactome analysis in two mouse models of AT-1 dysregulation (AT-1 sTg and AT-1S113R/+), co-immunoprecipitation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interactome in two genetic mouse models, single lab, Co-IP validation","pmids":["33870132"],"is_preprint":false},{"year":2022,"finding":"Molecular dynamics simulations starting from cryo-EM structures show that Sec62 binding to Sec61 alters the conformational dynamics of the lateral gate, plug, and pore region: the luminal lateral gate adopts a wider (open) conformation when Sec62 is bound, while it closes in the apo state; the signal peptide stabilizes the active state conformation during post-translational translocation.","method":"Molecular dynamics simulations from cryo-EM structures of Sec61 with and without Sec62","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational simulation only, no experimental validation in this paper","pmids":["36116515"],"is_preprint":false},{"year":2022,"finding":"Sec62 promotes gastric cancer metastasis by binding LC3II and activating autophagy via the UPR-related PERK/ATF4 pathway with concomitant upregulation of FIP200/Beclin-1/Atg5; autophagy activation in turn alters TIMP-1/MMP2/9 balance to promote migration and invasion.","method":"Co-immunoprecipitation of Sec62 with LC3II, transmission electron microscopy for autophagy, mRFP-GFP-LC3 adenovirus reporter, siRNA knockdown, xenograft models","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus autophagy flux reporter and in vivo xenograft, single lab, multiple orthogonal methods","pmids":["35165763"],"is_preprint":false},{"year":2025,"finding":"SEC62 interacts directly with ATAD3B at mitochondria-associated membranes (MAMs), leading to downregulation of ATAD3B expression, defective mitophagy, increased mitochondrial ROS, and inflammatory responses; hepatocyte-specific SEC62 overexpression worsens and SEC62 knockout ameliorates MASH pathology.","method":"Co-immunoprecipitation of SEC62 with ATAD3B, hepatocyte-specific overexpression and knockout mouse models, mitophagy and ROS assays","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying direct interaction plus in vivo genetic models, single lab","pmids":["42001994"],"is_preprint":false},{"year":2025,"finding":"Cinobufagin directly binds SEC62 (validated by MST and CETSA); SEC62 interacts with TRPM4 (validated by SPR) and promotes its ubiquitination and proteasomal degradation; cinobufagin disrupts the SEC62/TRPM4 interaction, stabilizing TRPM4 and enabling NECSO cell death in bortezomib-resistant multiple myeloma cells.","method":"LiP-MS, molecular docking, MST and CETSA binding assays, SPR for SEC62-TRPM4 interaction, immunoprecipitation for ubiquitination, SEC62 knockdown rescue experiments","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays (MST, CETSA, SPR) plus functional rescue, single lab","pmids":["40839992"],"is_preprint":false},{"year":2026,"finding":"SEC62-mediated ER-phagy activation in neurons alleviates Alzheimer's disease pathology (Aβ plaque deposition, neuroinflammation, cognitive impairment) in 5×FAD mice; ER-phagy receptor expression including SEC62 is decreased in AD patient iPSC-derived neurons and 5×FAD samples.","method":"AAV-mediated overexpression of SEC62 in 5×FAD mouse brain via intrathecal injection, Aβ plaque quantification, cognitive behavioral tests, iPSC-derived neuron analysis","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV gain-of-function with defined phenotypic readouts in AD mouse model, single lab","pmids":["42026868"],"is_preprint":false}],"current_model":"SEC62 encodes a two-pass ER transmembrane protein that serves dual functions: (1) as a component of the Sec61 translocon complex, where it (together with Sec63) stepwise gates the Sec61 channel for post-translational protein import into the ER—particularly for small proteins with slowly gating signal peptides—by displacing the plug domain and keeping the lateral gate open, a function regulated by CK2-mediated phosphorylation of Sec63 enhancing Sec62-Sec63 binding and by the SRP receptor displacing Sec62 to switch the translocon to cotranslational mode; and (2) as an ER-resident autophagy receptor (recovER-phagy) during ER stress recovery, where its C-terminal cytosolic LC3-interacting region (LIR) is required to selectively deliver excess ER components to autolysosomes, maintain ER homeostasis, and regulate ER Ca2+ leak via direct Ca2+-sensitive interaction with Sec61, with overexpression conferring stress tolerance, enhanced cell migration, and oncogenic properties linked to 3q26 amplification in multiple cancer types."},"narrative":{"mechanistic_narrative":"SEC62 encodes a two-pass ER transmembrane protein with cytosolic N- and C-termini that functions as an accessory component of the Sec61 translocon, originally defined in yeast as a membrane-intrinsic factor required for post-translational import of secretory precursors into the ER [PMID:2687286]. In mammalian cells, SEC62 acts together with SEC63 to drive the post-translational, SRP-independent translocation pathway—selectively required for signal-peptide-containing precursors, particularly small proteins (≤100 aa) with slowly gating signal peptides and downstream positively charged residues, in an ATP-dependent manner—while SEC61 itself serves both co- and post-translational routes [PMID:22375059, PMID:22648169, PMID:32133789]. Cryo-EM structures show that SEC63 first partially opens the Sec61 lateral gate and SEC62 then displaces the plug domain to open the translocation pore, with SEC62 binding altering lateral-gate, plug, and pore dynamics [PMID:33398175]. SEC62 engagement with the translocon is governed by the nascent chain and is regulated by CK2 phosphorylation of SEC63 (which enhances SEC62–SEC63 binding) and by the SRP receptor, whose SRα charged linker displaces SEC62 to switch the channel to cotranslational mode [PMID:23287549, PMID:25801167, PMID:26634806]. Independently of translocation, SEC62 serves as an ER-resident autophagy receptor during recovery from ER stress (recovER-phagy): a conserved C-terminal cytosolic LC3-interacting region selectively delivers ER components to autolysosomes, a function dispensable for its translocation role [PMID:27749824]. SEC62 also directly binds the Sec61 complex in a Ca2+-sensitive manner to limit ER Ca2+ leak [PMID:24304694]. SEC62 (TLOC1) is amplified at 3q26 and required for proliferation of amplified cell lines, conferring anchorage-independent growth via DDX3X binding, and promotes cancer progression through interactions including β-catenin (Wnt activation) and LC3II-driven autophagy [PMID:23764425, PMID:33858476, PMID:35165763].","teleology":[{"year":1989,"claim":"Established SEC62 as a membrane-intrinsic factor required for protein import into the ER, defining the post-translational translocation problem.","evidence":"In vitro translocation assays with mutant vs. wild-type yeast membranes and cytosol; sequence analysis predicting two TM domains","pmids":["2687286"],"confidence":"High","gaps":["Did not define the molecular partners or mechanism of channel gating","Mammalian relevance unaddressed"]},{"year":2000,"claim":"Showed the mammalian translocon includes ribosome-free Sec61 complexes associated with Sec62 and Sec63, extending the yeast paradigm to humans.","evidence":"Biochemical fractionation and co-isolation of ribosome-free Sec61 complexes with homology analysis","pmids":["10799540"],"confidence":"Medium","gaps":["Functional roles of the mammalian complex not yet dissected","Stoichiometry and architecture undefined"]},{"year":2012,"claim":"Dissected pathway specificity, establishing SEC62 as selectively required for post-translational translocation of signal-peptide precursors, especially small (≤100 aa) ATP-dependent substrates, distinct from SEC61 and SEC63 roles.","evidence":"siRNA knockdown in human cells with substrate-specific in vitro translocation assays and size-class analysis","pmids":["22375059","22648169"],"confidence":"High","gaps":["Structural basis of substrate selection not yet resolved","Signal peptide features determining SEC62 dependence not yet defined"]},{"year":2012,"claim":"Identified CK2 phosphorylation of SEC63 as a regulatory input enhancing SEC62–SEC63 binding required for functional translocation.","evidence":"CK2 phosphosite mapping with deletion/peptide approaches plus reciprocal Co-IP","pmids":["23287549"],"confidence":"Medium","gaps":["In vivo consequences of phosphosite mutation on translocation flux not quantified","Single lab"]},{"year":2013,"claim":"Revealed a Ca2+-sensitive direct SEC62–Sec61 interaction controlling ER Ca2+ leak, linking the translocon accessory to Ca2+ homeostasis.","evidence":"Biacore SPR Ca2+-sensitive binding, Ca2+ imaging, siRNA silencing, mutant SEC62 expression","pmids":["24304694"],"confidence":"Medium","gaps":["Structural detail of the Ca2+-binding motif unresolved","Relationship to translocation gating unclear"]},{"year":2013,"claim":"Connected SEC62 to oncogenesis, showing it is required for proliferation of 3q26-amplified cells and drives transformation through DDX3X binding.","evidence":"Loss/gain-of-function genetic screens, proteomic binding studies, anchorage-independent growth assays","pmids":["23764425"],"confidence":"Medium","gaps":["Mechanism linking translocon function to transformation not defined","DDX3X-dependent downstream pathway unmapped"]},{"year":2014,"claim":"Extended SEC62-SEC63 function to membrane-protein topogenesis, showing the complex facilitates C-terminal translocation of single- and multi-spanning proteins in yeast.","evidence":"Systematic yeast mutant analysis of membrane substrates with varying hydrophobicity, charge, and TM orientation","pmids":["23632075","25097231"],"confidence":"Medium","gaps":["Mammalian conservation of topogenic role untested","Single lab"]},{"year":2015,"claim":"Demonstrated that SEC62/63 engagement is dynamically controlled by the nascent chain and that the SRP receptor displaces SEC62 to switch the channel from post- to cotranslational mode.","evidence":"Ribosome-nascent chain isolation, MS, crosslinking, SRα truncation analysis and translocation assays","pmids":["25801167","26634806"],"confidence":"High","gaps":["Kinetics of the mode switch in living cells not quantified","Generality across substrate classes incomplete"]},{"year":2016,"claim":"Defined a translocation-independent role for SEC62 as an ER-phagy receptor during ER stress recovery via a C-terminal LIR motif.","evidence":"Autophagy flux assays, LC3-IP, LIR mutagenesis separating ER-phagy from translocation, live-cell imaging","pmids":["27749824"],"confidence":"High","gaps":["Signals triggering recovER-phagy onset not fully defined","Cargo selectivity mechanism within the ER unclear"]},{"year":2020,"claim":"Defined the signal-peptide features that dictate SEC62/SEC63 dependence, linking longer/less hydrophobic H-regions and downstream positive charges to slow channel gating and BiP requirement.","evidence":"Unbiased proteomics in intact human cells with SEC62/SEC63 knockdown and signal-peptide analysis of validated substrates","pmids":["32133789"],"confidence":"Medium","gaps":["Predictive rules not validated across full secretome","Single lab"]},{"year":2021,"claim":"Provided atomic mechanism for stepwise channel activation: SEC63 partially opens the lateral gate, SEC62 displaces the plug to open the pore.","evidence":"Cryo-EM structures of multiple Sec61-Sec62-Sec63 variants with MD simulations and mutagenesis","pmids":["33398175"],"confidence":"High","gaps":["Dynamic transition states captured only computationally","Mammalian complex structure not resolved here"]},{"year":2021,"claim":"Expanded SEC62's autophagy/cancer roles, showing β-catenin stabilization (Wnt activation) and ATG9A-dependent recruitment to ER-phagy.","evidence":"GST pull-down, Co-IP, knockdown and in vivo cancer assays; ATG9A interactome in mouse models","pmids":["33858476","33870132"],"confidence":"Medium","gaps":["Connection between translocon and Wnt functions of SEC62 unclear","ATG9A acetylation-to-recruitment mechanism not fully resolved"]},{"year":2022,"claim":"Linked SEC62-driven autophagy to cancer metastasis via LC3II binding and PERK/ATF4 UPR signaling, and computationally refined how SEC62 binding shifts channel conformational dynamics.","evidence":"Co-IP, autophagy flux reporters, xenografts; MD simulations from cryo-EM structures","pmids":["35165763","36116515"],"confidence":"Medium","gaps":["MD predictions of gate widening not experimentally validated in that work","Causality between autophagy and invasion incompletely separated"]},{"year":2025,"claim":"Identified disease-relevant SEC62 protein interactions: ATAD3B at mitochondria-associated membranes (driving MASH via defective mitophagy) and TRPM4 (whose degradation SEC62 promotes), the latter a druggable target of cinobufagin.","evidence":"Co-IP, hepatocyte-specific overexpression/knockout mice, MST/CETSA/SPR binding assays, ubiquitination assays","pmids":["42001994","40839992"],"confidence":"Medium","gaps":["How these interactions relate to canonical translocon/ER-phagy roles unclear","Single lab per interaction"]},{"year":2026,"claim":"Showed neuronal SEC62-mediated ER-phagy alleviates Alzheimer's pathology, linking ER-phagy receptor function to neurodegeneration.","evidence":"AAV-mediated SEC62 overexpression in 5×FAD mice, Aβ and cognitive readouts, iPSC-derived neuron analysis","pmids":["42026868"],"confidence":"Medium","gaps":["Mechanistic link between ER-phagy and Aβ clearance not fully defined","Single model system"]},{"year":null,"claim":"How SEC62's translocation, ER-phagy, Ca2+-regulation, and disease-associated interactions are integrated and switched within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified regulatory model coordinating SEC62's distinct functions","Mammalian translocon structural architecture not solved","Whether oncogenic interactions depend on translocon vs. ER-phagy activity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,4,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12,14]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,12]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12,16,18]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,4,14]}],"complexes":["Sec61-Sec62-Sec63 translocon complex"],"partners":["SEC61","SEC63","DDX3X","CTNNB1","MAP1LC3B","ATG9A","ATAD3B","TRPM4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99442","full_name":"Translocation protein SEC62","aliases":["Translocation protein 1","TP-1","hTP-1"],"length_aa":399,"mass_kda":45.9,"function":"Mediates post-translational transport of precursor polypeptides across endoplasmic reticulum (ER). Proposed to act as a targeting receptor for small presecretory proteins containing short and apolar signal peptides. Targets and properly positions newly synthesized presecretory proteins into the SEC61 channel-forming translocon complex, triggering channel opening for polypeptide translocation to the ER lumen","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q99442/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC62","classification":"Not Classified","n_dependent_lines":436,"n_total_lines":1208,"dependency_fraction":0.3609271523178808},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SEC61B","stoichiometry":10.0},{"gene":"ANKRD46","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SEC62","total_profiled":1310},"omim":[{"mim_id":"618271","title":"SEC61 TRANSLOCON, ALPHA-2 SUBUNIT; SEC61A2","url":"https://www.omim.org/entry/618271"},{"mim_id":"609214","title":"SEC61 TRANSLOCON, BETA SUBUNIT; SEC61B","url":"https://www.omim.org/entry/609214"},{"mim_id":"609213","title":"SEC61 TRANSLOCON, ALPHA-1 SUBUNIT; SEC61A1","url":"https://www.omim.org/entry/609213"},{"mim_id":"608648","title":"SEC63 HOMOLOG, PROTEIN TRANSLOCATION REGULATOR; SEC63","url":"https://www.omim.org/entry/608648"},{"mim_id":"602173","title":"SEC62 HOMOLOG, PREPROTEIN TRANSLOCATION FACTOR; SEC62","url":"https://www.omim.org/entry/602173"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Intermediate filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC62"},"hgnc":{"alias_symbol":["Dtrp1","HTP1"],"prev_symbol":["TLOC1"]},"alphafold":{"accession":"Q99442","domains":[{"cath_id":"-","chopping":"1-102_166-191","consensus_level":"medium","plddt":83.0895,"start":1,"end":191},{"cath_id":"1.10.287","chopping":"219-285","consensus_level":"high","plddt":80.5343,"start":219,"end":285}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99442","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99442-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99442-F1-predicted_aligned_error_v6.png","plddt_mean":65.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC62","jax_strain_url":"https://www.jax.org/strain/search?query=SEC62"},"sequence":{"accession":"Q99442","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99442.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99442/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99442"}},"corpus_meta":[{"pmid":"27749824","id":"PMC_27749824","title":"Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery.","date":"2016","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27749824","citation_count":379,"is_preprint":false},{"pmid":"33858476","id":"PMC_33858476","title":"Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33858476","citation_count":159,"is_preprint":false},{"pmid":"10799540","id":"PMC_10799540","title":"Mammalian Sec61 is associated with Sec62 and Sec63.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10799540","citation_count":158,"is_preprint":false},{"pmid":"2687286","id":"PMC_2687286","title":"SEC62 encodes a putative membrane protein required for protein translocation into the yeast endoplasmic reticulum.","date":"1989","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/2687286","citation_count":156,"is_preprint":false},{"pmid":"29263911","id":"PMC_29263911","title":"Let's talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine.","date":"2017","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29263911","citation_count":140,"is_preprint":false},{"pmid":"22375059","id":"PMC_22375059","title":"Different effects of Sec61α, Sec62 and Sec63 depletion on transport of polypeptides into the endoplasmic reticulum of mammalian cells.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22375059","citation_count":134,"is_preprint":false},{"pmid":"16291647","id":"PMC_16291647","title":"HTP-1 coordinates synaptonemal complex assembly with homolog alignment during meiosis in C. elegans.","date":"2005","source":"Genes & 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membranes from sec62 mutant cells display low and labile translocation activity, while cytosol from mutant cells supports normal translocation, demonstrating the defect is membrane-intrinsic.\",\n      \"method\": \"In vitro translocation assay with membranes/cytosol from mutant and wild-type yeast; DNA sequence analysis predicting two transmembrane domains and cytoplasmic N- and C-terminal domains\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution assay with defined mutant membranes vs. cytosol, replicated across multiple substrates, foundational study\",\n      \"pmids\": [\"2687286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mammalian Sec61 exists in ribosome-free complexes associated with Sec62 and Sec63 (homologs of yeast Sec62p/Sec63p), forming a higher-order translocon complex in the ER membrane.\",\n      \"method\": \"Biochemical fractionation, primary sequence homology analysis, co-isolation of ribosome-free Sec61 complexes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation identifying complex components, single lab, sequence homology corroborating functional assignment\",\n      \"pmids\": [\"10799540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human Sec62 has gained an evolutionary function absent in yeast: it interacts with the ribosomal tunnel exit and supports cotranslational protein transport into the ER. Sec62 is associated with ribosomes in human cells and interacts with Sec63.\",\n      \"method\": \"Ribosome co-sedimentation, co-immunoprecipitation of Sec62 with Sec63 and ribosomes, comparison with yeast ortholog\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and co-sedimentation, single lab, two orthogonal methods\",\n      \"pmids\": [\"20071467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Silencing SEC62 in human cells specifically inhibits post-translational transport of signal-peptide-containing precursor proteins into the ER, whereas silencing SEC61A1 inhibits both co- and post-translational transport; Sec63 depletion affects the initial phase of co-translational transport.\",\n      \"method\": \"siRNA knockdown in HeLa cells, in vitro translocation assay with semi-permeabilized cells, substrate-specific analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro translocation assay with defined knockdowns and multiple substrates, clean mechanistic dissection of pathway specificity\",\n      \"pmids\": [\"22375059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sec62 is required for efficient post-translational translocation of small proteins (≤100 amino acids) with N-terminal signal sequences in mammalian cells; this Sec62-dependent pathway operates via the Sec61 translocon and requires ATP, functioning as a fail-safe mechanism independent of SRP.\",\n      \"method\": \"siRNA knockdown of Sec62 and SRP pathway components, in vitro translocation assays, size-class analysis of substrates\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution/translocation assays with defined substrates and ATP requirement tested, multiple substrate classes analyzed\",\n      \"pmids\": [\"22648169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CK2 phosphorylates Sec63 at serine residues 574, 576, and 748, and this phosphorylation enhances the binding of Sec63 to Sec62, a prerequisite for functional ER protein translocation.\",\n      \"method\": \"CK2 phosphorylation mapping with deletion mutants and peptide library; pull-down assays and co-immunoprecipitation of Sec63 with Sec62\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical phosphorylation mapping plus reciprocal Co-IP, single lab, two orthogonal methods\",\n      \"pmids\": [\"23287549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SEC62 (TLOC1) is selectively required for proliferation of cell lines with 3q26 amplification; increased TLOC1 expression induces anchorage-independent growth; TLOC1 binds DDX3X, which is essential for TLOC1-induced cellular transformation.\",\n      \"method\": \"Loss- and gain-of-function genetic screens, proteomic binding studies identifying DDX3X interaction, anchorage-independent growth assays\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic interaction study plus functional rescue with DDX3X requirement, single lab\",\n      \"pmids\": [\"23764425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sec62 directly interacts with the Sec61 complex in a Ca2+-sensitive manner; a Ca2+-binding motif in Sec62 is essential for its molecular function in regulating Ca2+ leakage through Sec61; SEC62 silencing elevates cytosolic Ca2+ and increases ER Ca2+ leakage after thapsigargin treatment.\",\n      \"method\": \"Biacore surface plasmon resonance (Ca2+-sensitive interaction assay), Ca2+ imaging, siRNA silencing, mutant SEC62 expression\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Biacore direct binding assay plus Ca2+ imaging, single lab, two orthogonal methods\",\n      \"pmids\": [\"24304694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In yeast, mutations in the N-terminal cytosolic domain of Sec62 impair its interaction with Sec63 and cause defects in membrane insertion and translocation of the C-terminus of membrane proteins, revealing a role for Sec62-Sec63 in topogenesis of membrane proteins.\",\n      \"method\": \"Yeast mutant analysis, systematic analysis of membrane proteins with varying hydrophobicity and topology, in vivo translocation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutant analysis with multiple substrates, single lab\",\n      \"pmids\": [\"23632075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The Sec62-Sec63 complex facilitates translocation of the C-terminus of membrane proteins in yeast; mutations in the N-terminal cytosolic domain of Sec62 disrupt Sec62-Sec63 interaction and impair C-terminal translocation of single- and multi-spanning membrane proteins.\",\n      \"method\": \"Systematic analysis of single and multi-spanning membrane proteins with varying hydrophobicity, flanking charges, and TM orientation in yeast sec62 mutant strains\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic genetic analysis with multiple model substrates, single lab\",\n      \"pmids\": [\"25097231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Blocking cotranslational translocation by passenger domain folding stabilizes an alternate translocon complex containing Sec61, Sec62, and Sec63; Sec62/63 stabilization within the translocon also occurs for native endogenous substrates (e.g., prion protein) and correlates with a delay in translocation initiation, demonstrating that Sec62/63 engagement is controlled by the nascent chain.\",\n      \"method\": \"Ribosome-nascent chain isolation, mass spectrometry of translocon complexes, crosslinking, cotranslational translocation assays with preprolactin and prion protein as substrates\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of translocon complexes, MS identification, crosslinking, and functional translocation assays in a single study with multiple substrates\",\n      \"pmids\": [\"25801167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The SRP receptor (SR) switches the Sec61 translocon from Sec62-dependent to SRP-dependent translocation by displacing Sec62 from Sec61; the charged linker region of SRα mediates this displacement, while a separate conserved element promotes ribosome binding.\",\n      \"method\": \"Truncation variant analysis of SRα, crosslinking assays, in vitro translocation assays demonstrating Sec62 displacement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — crosslinking plus translocation assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"26634806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sec62 functions as an ER-resident autophagy receptor during recovery from ER stress (recovER-phagy), selectively delivering ER components to autolysosomes; this requires a conserved LC3-interacting region (LIR) in the C-terminal cytosolic domain of Sec62, which is dispensable for protein translocation function.\",\n      \"method\": \"Autophagy flux assays, LC3-IP, LIR motif mutagenesis, live-cell imaging, fractionation, loss-of-function experiments in mammalian cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — LIR mutagenesis separating ER-phagy from translocation function, LC3 interaction validated biochemically, multiple orthogonal methods, high-impact journal\",\n      \"pmids\": [\"27749824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human Sec62/Sec63 substrates share signal peptides with longer but less hydrophobic hydrophobic regions and lower C-region polarity; a slowly gating signal peptide combined with a downstream positively charged amino acid cluster is decisive for Sec62/Sec63 requirement, and these features also correlate with BiP requirement and sensitivity to the Sec61-channel inhibitor CAM741.\",\n      \"method\": \"Unbiased proteomics approach in intact human cells, siRNA knockdown of SEC62/SEC63, substrate signal peptide analysis of 22 newly identified substrates\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics with defined knockdowns in intact cells, multiple substrates validated, single lab\",\n      \"pmids\": [\"32133789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of Sec61-Sec62-Sec63 complexes from yeast show that Sec63 and Sec62 stepwise activate Sec61 for post-translational translocation: Sec63 first partially opens the lateral gate via cytosolic and luminal domain interactions with Sec61, then Sec62 is required to displace the plug domain to open the translocation pore; Sec62 may also prevent lipids from entering the channel through the open lateral gate.\",\n      \"method\": \"Cryo-EM structure determination of multiple complex variants, molecular dynamics simulations, functional mutagenesis analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures at atomic detail combined with MD simulations and mutagenesis, multiple complex variants, high-impact structural biology journal\",\n      \"pmids\": [\"33398175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sec62 promotes stemness and chemoresistance of colorectal cancer cells by binding to β-catenin, inhibiting its degradation, and competitively disrupting the interaction between β-catenin and APC, thereby inhibiting β-catenin destruction complex assembly and activating Wnt signaling.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, western blot, siRNA knockdown, in vitro and in vivo functional experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pull-down plus reciprocal Co-IP demonstrating direct interaction and APC displacement, single lab\",\n      \"pmids\": [\"33858476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATG9A engages SEC62 (and FAM134B) on the cytosolic side of the ER to induce reticulophagy; this engagement depends on the acetylation status of ATG9A in the ER lumen, linking luminal acetylation to cytosolic ER-phagy receptor recruitment.\",\n      \"method\": \"ATG9A interactome analysis in two mouse models of AT-1 dysregulation (AT-1 sTg and AT-1S113R/+), co-immunoprecipitation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interactome in two genetic mouse models, single lab, Co-IP validation\",\n      \"pmids\": [\"33870132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Molecular dynamics simulations starting from cryo-EM structures show that Sec62 binding to Sec61 alters the conformational dynamics of the lateral gate, plug, and pore region: the luminal lateral gate adopts a wider (open) conformation when Sec62 is bound, while it closes in the apo state; the signal peptide stabilizes the active state conformation during post-translational translocation.\",\n      \"method\": \"Molecular dynamics simulations from cryo-EM structures of Sec61 with and without Sec62\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational simulation only, no experimental validation in this paper\",\n      \"pmids\": [\"36116515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sec62 promotes gastric cancer metastasis by binding LC3II and activating autophagy via the UPR-related PERK/ATF4 pathway with concomitant upregulation of FIP200/Beclin-1/Atg5; autophagy activation in turn alters TIMP-1/MMP2/9 balance to promote migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation of Sec62 with LC3II, transmission electron microscopy for autophagy, mRFP-GFP-LC3 adenovirus reporter, siRNA knockdown, xenograft models\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus autophagy flux reporter and in vivo xenograft, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35165763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC62 interacts directly with ATAD3B at mitochondria-associated membranes (MAMs), leading to downregulation of ATAD3B expression, defective mitophagy, increased mitochondrial ROS, and inflammatory responses; hepatocyte-specific SEC62 overexpression worsens and SEC62 knockout ameliorates MASH pathology.\",\n      \"method\": \"Co-immunoprecipitation of SEC62 with ATAD3B, hepatocyte-specific overexpression and knockout mouse models, mitophagy and ROS assays\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying direct interaction plus in vivo genetic models, single lab\",\n      \"pmids\": [\"42001994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cinobufagin directly binds SEC62 (validated by MST and CETSA); SEC62 interacts with TRPM4 (validated by SPR) and promotes its ubiquitination and proteasomal degradation; cinobufagin disrupts the SEC62/TRPM4 interaction, stabilizing TRPM4 and enabling NECSO cell death in bortezomib-resistant multiple myeloma cells.\",\n      \"method\": \"LiP-MS, molecular docking, MST and CETSA binding assays, SPR for SEC62-TRPM4 interaction, immunoprecipitation for ubiquitination, SEC62 knockdown rescue experiments\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays (MST, CETSA, SPR) plus functional rescue, single lab\",\n      \"pmids\": [\"40839992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC62-mediated ER-phagy activation in neurons alleviates Alzheimer's disease pathology (Aβ plaque deposition, neuroinflammation, cognitive impairment) in 5×FAD mice; ER-phagy receptor expression including SEC62 is decreased in AD patient iPSC-derived neurons and 5×FAD samples.\",\n      \"method\": \"AAV-mediated overexpression of SEC62 in 5×FAD mouse brain via intrathecal injection, Aβ plaque quantification, cognitive behavioral tests, iPSC-derived neuron analysis\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV gain-of-function with defined phenotypic readouts in AD mouse model, single lab\",\n      \"pmids\": [\"42026868\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC62 encodes a two-pass ER transmembrane protein that serves dual functions: (1) as a component of the Sec61 translocon complex, where it (together with Sec63) stepwise gates the Sec61 channel for post-translational protein import into the ER—particularly for small proteins with slowly gating signal peptides—by displacing the plug domain and keeping the lateral gate open, a function regulated by CK2-mediated phosphorylation of Sec63 enhancing Sec62-Sec63 binding and by the SRP receptor displacing Sec62 to switch the translocon to cotranslational mode; and (2) as an ER-resident autophagy receptor (recovER-phagy) during ER stress recovery, where its C-terminal cytosolic LC3-interacting region (LIR) is required to selectively deliver excess ER components to autolysosomes, maintain ER homeostasis, and regulate ER Ca2+ leak via direct Ca2+-sensitive interaction with Sec61, with overexpression conferring stress tolerance, enhanced cell migration, and oncogenic properties linked to 3q26 amplification in multiple cancer types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC62 encodes a two-pass ER transmembrane protein with cytosolic N- and C-termini that functions as an accessory component of the Sec61 translocon, originally defined in yeast as a membrane-intrinsic factor required for post-translational import of secretory precursors into the ER [#0]. In mammalian cells, SEC62 acts together with SEC63 to drive the post-translational, SRP-independent translocation pathway—selectively required for signal-peptide-containing precursors, particularly small proteins (\\u2264100 aa) with slowly gating signal peptides and downstream positively charged residues, in an ATP-dependent manner—while SEC61 itself serves both co- and post-translational routes [#3, #4, #13]. Cryo-EM structures show that SEC63 first partially opens the Sec61 lateral gate and SEC62 then displaces the plug domain to open the translocation pore, with SEC62 binding altering lateral-gate, plug, and pore dynamics [#14]. SEC62 engagement with the translocon is governed by the nascent chain and is regulated by CK2 phosphorylation of SEC63 (which enhances SEC62\\u2013SEC63 binding) and by the SRP receptor, whose SR\\u03b1 charged linker displaces SEC62 to switch the channel to cotranslational mode [#5, #10, #11]. Independently of translocation, SEC62 serves as an ER-resident autophagy receptor during recovery from ER stress (recovER-phagy): a conserved C-terminal cytosolic LC3-interacting region selectively delivers ER components to autolysosomes, a function dispensable for its translocation role [#12]. SEC62 also directly binds the Sec61 complex in a Ca2+-sensitive manner to limit ER Ca2+ leak [#7]. SEC62 (TLOC1) is amplified at 3q26 and required for proliferation of amplified cell lines, conferring anchorage-independent growth via DDX3X binding, and promotes cancer progression through interactions including \\u03b2-catenin (Wnt activation) and LC3II-driven autophagy [#6, #15, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established SEC62 as a membrane-intrinsic factor required for protein import into the ER, defining the post-translational translocation problem.\",\n      \"evidence\": \"In vitro translocation assays with mutant vs. wild-type yeast membranes and cytosol; sequence analysis predicting two TM domains\",\n      \"pmids\": [\"2687286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular partners or mechanism of channel gating\", \"Mammalian relevance unaddressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed the mammalian translocon includes ribosome-free Sec61 complexes associated with Sec62 and Sec63, extending the yeast paradigm to humans.\",\n      \"evidence\": \"Biochemical fractionation and co-isolation of ribosome-free Sec61 complexes with homology analysis\",\n      \"pmids\": [\"10799540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional roles of the mammalian complex not yet dissected\", \"Stoichiometry and architecture undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Dissected pathway specificity, establishing SEC62 as selectively required for post-translational translocation of signal-peptide precursors, especially small (\\u2264100 aa) ATP-dependent substrates, distinct from SEC61 and SEC63 roles.\",\n      \"evidence\": \"siRNA knockdown in human cells with substrate-specific in vitro translocation assays and size-class analysis\",\n      \"pmids\": [\"22375059\", \"22648169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of substrate selection not yet resolved\", \"Signal peptide features determining SEC62 dependence not yet defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified CK2 phosphorylation of SEC63 as a regulatory input enhancing SEC62\\u2013SEC63 binding required for functional translocation.\",\n      \"evidence\": \"CK2 phosphosite mapping with deletion/peptide approaches plus reciprocal Co-IP\",\n      \"pmids\": [\"23287549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo consequences of phosphosite mutation on translocation flux not quantified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a Ca2+-sensitive direct SEC62\\u2013Sec61 interaction controlling ER Ca2+ leak, linking the translocon accessory to Ca2+ homeostasis.\",\n      \"evidence\": \"Biacore SPR Ca2+-sensitive binding, Ca2+ imaging, siRNA silencing, mutant SEC62 expression\",\n      \"pmids\": [\"24304694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural detail of the Ca2+-binding motif unresolved\", \"Relationship to translocation gating unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected SEC62 to oncogenesis, showing it is required for proliferation of 3q26-amplified cells and drives transformation through DDX3X binding.\",\n      \"evidence\": \"Loss/gain-of-function genetic screens, proteomic binding studies, anchorage-independent growth assays\",\n      \"pmids\": [\"23764425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking translocon function to transformation not defined\", \"DDX3X-dependent downstream pathway unmapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended SEC62-SEC63 function to membrane-protein topogenesis, showing the complex facilitates C-terminal translocation of single- and multi-spanning proteins in yeast.\",\n      \"evidence\": \"Systematic yeast mutant analysis of membrane substrates with varying hydrophobicity, charge, and TM orientation\",\n      \"pmids\": [\"23632075\", \"25097231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian conservation of topogenic role untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that SEC62/63 engagement is dynamically controlled by the nascent chain and that the SRP receptor displaces SEC62 to switch the channel from post- to cotranslational mode.\",\n      \"evidence\": \"Ribosome-nascent chain isolation, MS, crosslinking, SR\\u03b1 truncation analysis and translocation assays\",\n      \"pmids\": [\"25801167\", \"26634806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of the mode switch in living cells not quantified\", \"Generality across substrate classes incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a translocation-independent role for SEC62 as an ER-phagy receptor during ER stress recovery via a C-terminal LIR motif.\",\n      \"evidence\": \"Autophagy flux assays, LC3-IP, LIR mutagenesis separating ER-phagy from translocation, live-cell imaging\",\n      \"pmids\": [\"27749824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals triggering recovER-phagy onset not fully defined\", \"Cargo selectivity mechanism within the ER unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the signal-peptide features that dictate SEC62/SEC63 dependence, linking longer/less hydrophobic H-regions and downstream positive charges to slow channel gating and BiP requirement.\",\n      \"evidence\": \"Unbiased proteomics in intact human cells with SEC62/SEC63 knockdown and signal-peptide analysis of validated substrates\",\n      \"pmids\": [\"32133789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Predictive rules not validated across full secretome\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided atomic mechanism for stepwise channel activation: SEC63 partially opens the lateral gate, SEC62 displaces the plug to open the pore.\",\n      \"evidence\": \"Cryo-EM structures of multiple Sec61-Sec62-Sec63 variants with MD simulations and mutagenesis\",\n      \"pmids\": [\"33398175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamic transition states captured only computationally\", \"Mammalian complex structure not resolved here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded SEC62's autophagy/cancer roles, showing \\u03b2-catenin stabilization (Wnt activation) and ATG9A-dependent recruitment to ER-phagy.\",\n      \"evidence\": \"GST pull-down, Co-IP, knockdown and in vivo cancer assays; ATG9A interactome in mouse models\",\n      \"pmids\": [\"33858476\", \"33870132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection between translocon and Wnt functions of SEC62 unclear\", \"ATG9A acetylation-to-recruitment mechanism not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked SEC62-driven autophagy to cancer metastasis via LC3II binding and PERK/ATF4 UPR signaling, and computationally refined how SEC62 binding shifts channel conformational dynamics.\",\n      \"evidence\": \"Co-IP, autophagy flux reporters, xenografts; MD simulations from cryo-EM structures\",\n      \"pmids\": [\"35165763\", \"36116515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MD predictions of gate widening not experimentally validated in that work\", \"Causality between autophagy and invasion incompletely separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified disease-relevant SEC62 protein interactions: ATAD3B at mitochondria-associated membranes (driving MASH via defective mitophagy) and TRPM4 (whose degradation SEC62 promotes), the latter a druggable target of cinobufagin.\",\n      \"evidence\": \"Co-IP, hepatocyte-specific overexpression/knockout mice, MST/CETSA/SPR binding assays, ubiquitination assays\",\n      \"pmids\": [\"42001994\", \"40839992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How these interactions relate to canonical translocon/ER-phagy roles unclear\", \"Single lab per interaction\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed neuronal SEC62-mediated ER-phagy alleviates Alzheimer's pathology, linking ER-phagy receptor function to neurodegeneration.\",\n      \"evidence\": \"AAV-mediated SEC62 overexpression in 5\\u00d7FAD mice, A\\u03b2 and cognitive readouts, iPSC-derived neuron analysis\",\n      \"pmids\": [\"42026868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between ER-phagy and A\\u03b2 clearance not fully defined\", \"Single model system\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEC62's translocation, ER-phagy, Ca2+-regulation, and disease-associated interactions are integrated and switched within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified regulatory model coordinating SEC62's distinct functions\", \"Mammalian translocon structural architecture not solved\", \"Whether oncogenic interactions depend on translocon vs. ER-phagy activity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 4, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 14]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 16, 18]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 4, 14]}\n    ],\n    \"complexes\": [\"Sec61-Sec62-Sec63 translocon complex\"],\n    \"partners\": [\"SEC61\", \"SEC63\", \"DDX3X\", \"CTNNB1\", \"MAP1LC3B\", \"ATG9A\", \"ATAD3B\", \"TRPM4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}