{"gene":"KRTCAP2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2005,"finding":"KCP2 (KRTCAP2), a 14 kDa protein, was co-purified with the mammalian oligosaccharyltransferase (OST) complex from solubilized, actively engaged ribosomes, identifying it as a potential new OST subunit with no previously known function.","method":"2D Blue Native PAGE/SDS-PAGE and mass spectrometry co-purification from ribosome translocon complexes","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry-based co-purification is rigorous but single lab; no functional follow-up in this paper","pmids":["15835887"],"is_preprint":false},{"year":2012,"finding":"Human KCP2 is an integral membrane protein with three transmembrane spans resulting from alternative initiation of translation, localizes to the endoplasmic reticulum via a functional KKxx retrieval signal at its cytosolic C-terminus, and assembles into a ~500 kDa OST complex predominantly containing the catalytic STT3A isoform; co-immunoprecipitation confirmed robust physical interaction with STT3A and weaker associations with STT3B and OST48.","method":"Alternative translation initiation characterization, ER localization by immunofluorescence, native gel analysis, co-immunoprecipitation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (topology mapping, localization, native gel, Co-IP) in a single focused mechanistic study","pmids":["22266900"],"is_preprint":false},{"year":2012,"finding":"KCP2 depletion causes substrate-specific hypoglycosylation (not global OST disruption) and leads to accumulation of a novel STT3A-containing OST subcomplex, suggesting KCP2 selectively enhances OST-dependent processing of specific co-translational substrates of STT3A-containing complexes; by contrast, OST48 and DAD1 knockdown globally destabilizes both STT3A- and STT3B-containing complexes.","method":"siRNA knockdown, glycosylation assays, native gel electrophoresis, subunit-specific depletion analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, glycosylation assay, native gel) in single focused mechanistic study; distinct KCP2 phenotype from other OST subunits clearly established","pmids":["22467853"],"is_preprint":false},{"year":2011,"finding":"KCP2 (together with DC2) depletion affects APP (amyloid precursor protein) processing in a substrate-specific manner: knockdown leads to accumulation of C-terminal fragments C99 and C83 and reduced full-length mature APP, and specifically reduces the active PS1 fragment of the γ-secretase complex blocking Aβ production; conversely, overexpression of KCP2 increases the active γ-secretase complex and stimulates Aβ production, indicating KCP2 interacts with and modulates the γ-secretase pathway.","method":"siRNA knockdown, overexpression, Western blot analysis of APP processing intermediates, γ-secretase activity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with specific mechanistic readouts, single lab, two orthogonal perturbations","pmids":["21768116"],"is_preprint":false},{"year":2017,"finding":"DC2 and KCP2 mediate the physical interaction between the STT3A-containing OST complex and the Sec61 protein translocation channel; loss of DC2 causes a co-translational N-glycosylation defect mimicking the STT3A phenotype, while DC2- and KCP2-deficient STT3A complexes remain stable and enzymatically active, demonstrating these subunits are specifically required for translocon association rather than for OST catalytic activity.","method":"CRISPR/genome-edited human cell lines deficient in DC2 or KCP2, biochemical fractionation, co-immunoprecipitation, deletion mutagenesis of DC2 functional motifs, N-glycosylation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetically modified human cells with multiple orthogonal biochemical approaches plus mutagenesis; directly establishes mechanism","pmids":["28860277"],"is_preprint":false},{"year":2017,"finding":"KCP2 was identified as a binding partner of selenoprotein T (SelT) in a yeast membrane protein interaction screen, and SelT interacts with KCP2 and other subunits of the A-type OST complex; SelT knockdown depletes A-type OST subunits including KCP2 and causes POMC N-glycosylation defects, positioning SelT as a novel subunit required for A-type OST complex integrity.","method":"Split-ubiquitin yeast two-hybrid screen, co-immunoprecipitation, SelT siRNA knockdown with N-glycosylation readout","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus Co-IP plus functional knockdown; single lab; KCP2 role here is as interacting partner rather than primary subject","pmids":["28928140"],"is_preprint":false},{"year":2013,"finding":"KCP2 was identified as a binding partner of the Na+/Mg2+ exchanger SLC41A1 in a split-ubiquitin yeast two-hybrid screen; the interaction was categorized as forming a transient rather than stable complex, and KCP2 was proposed to contribute to SLC41A1 production, folding, or maturation in the ER.","method":"Split-ubiquitin yeast two-hybrid assay (polyton — appeared more than once in screen); interaction not confirmed by mass spectrometry","journal":"Magnesium research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid screen, not confirmed by orthogonal method, single lab","pmids":["23823179"],"is_preprint":false},{"year":2026,"finding":"KRTCAP2 depletion in glioma cells inhibited proliferation, migration, and invasion, while overexpression promoted these malignant behaviors; KRTCAP2 expression was positively associated with infiltration of CD68+ and CD163+ tumor-associated macrophages, indicating a role in promoting an immunosuppressive tumor microenvironment.","method":"siRNA/shRNA knockdown and overexpression in glioma cell lines, in vitro functional assays (proliferation, migration, invasion), multiplex immunohistochemistry for immune cell co-localization, drug sensitivity (apoptosis) assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vitro loss- and gain-of-function with defined cellular phenotypes and immune cell association; single lab, no mechanistic pathway placement beyond N-glycosylation inference","pmids":["41676149"],"is_preprint":false}],"current_model":"KRTCAP2 (KCP2) is a non-catalytic integral membrane subunit of the mammalian STT3A-containing oligosaccharyltransferase (OST) complex in the ER, where it localizes via a KKxx retrieval signal; together with DC2, it physically bridges the STT3A-OST complex to the Sec61 protein translocation channel to enable co-translational N-glycosylation of specific substrates, while also modulating γ-secretase activity and APP processing, and promoting glioma cell proliferation, migration, and immunosuppression."},"narrative":{"mechanistic_narrative":"KRTCAP2 (KCP2) is a small, non-catalytic integral membrane subunit of the mammalian STT3A-containing oligosaccharyltransferase (OST) complex that supports co-translational N-glycosylation in the endoplasmic reticulum [PMID:15835887, PMID:22266900]. It is an integral membrane protein with three transmembrane spans generated by alternative translation initiation, and it is retained in the ER via a functional KKxx retrieval signal at its cytosolic C-terminus, assembling into a ~500 kDa complex built around the catalytic STT3A isoform with which it interacts robustly [PMID:22266900]. Rather than contributing to OST catalysis, KCP2 together with DC2 physically bridges the STT3A-OST complex to the Sec61 translocation channel, and KCP2-deficient complexes remain stable and enzymatically active [PMID:28860277]; consistent with this dedicated role, its loss produces substrate-specific hypoglycosylation and accumulation of an STT3A-containing subcomplex rather than the global OST destabilization seen when core subunits are depleted [PMID:22467853]. KCP2 also modulates γ-secretase activity and APP processing, with depletion causing accumulation of the C99/C83 fragments and reduced Aβ production and overexpression stimulating active γ-secretase and Aβ generation [PMID:21768116]. In glioma cells, KRTCAP2 promotes proliferation, migration, and invasion and is associated with tumor-associated macrophage infiltration and an immunosuppressive microenvironment [PMID:41676149].","teleology":[{"year":2005,"claim":"Established that an uncharacterized 14 kDa protein physically associates with the translation/translocation machinery, raising the possibility of a new OST subunit.","evidence":"Blue Native/SDS-PAGE and mass spectrometry co-purification from ribosome-translocon complexes","pmids":["15835887"],"confidence":"Medium","gaps":["No functional role assigned","Membership in OST not yet confirmed by orthogonal methods"]},{"year":2011,"claim":"Linked KCP2 to a specific cellular pathway by showing it modulates APP processing and γ-secretase activity, indicating substrate-specific regulatory influence.","evidence":"siRNA knockdown, overexpression, and Western analysis of APP intermediates plus γ-secretase activity assays","pmids":["21768116"],"confidence":"Medium","gaps":["Direct physical interaction with γ-secretase components not resolved","Mechanistic link to its OST/glycosylation function not established"]},{"year":2012,"claim":"Defined KCP2 topology, ER localization, and complex membership, establishing it as a bona fide subunit of the STT3A-containing OST.","evidence":"Alternative initiation mapping, immunofluorescence, native gel analysis, and co-immunoprecipitation","pmids":["22266900"],"confidence":"High","gaps":["Functional contribution to glycosylation not yet defined","Basis for STT3A preference unknown"]},{"year":2012,"claim":"Distinguished KCP2 from core OST subunits by showing its loss causes substrate-specific hypoglycosylation and a stable subcomplex rather than global complex collapse.","evidence":"siRNA knockdown with glycosylation assays, native gel electrophoresis, and subunit-specific depletion comparison","pmids":["22467853"],"confidence":"High","gaps":["Identity of the affected substrate set not fully defined","Mechanism of selectivity unresolved"]},{"year":2017,"claim":"Resolved the functional role by demonstrating that KCP2 and DC2 tether the STT3A-OST to the Sec61 channel and are required for translocon association, not catalysis.","evidence":"CRISPR-edited human cells, biochemical fractionation, Co-IP, deletion mutagenesis, and N-glycosylation assays","pmids":["28860277"],"confidence":"High","gaps":["Structural details of the OST-Sec61 bridge not defined","Relative contributions of KCP2 versus DC2 not dissected"]},{"year":2017,"claim":"Placed KCP2 within the broader A-type OST interactome by identifying SelT as a partner whose loss depletes KCP2 and impairs N-glycosylation.","evidence":"Split-ubiquitin yeast two-hybrid screen, Co-IP, and SelT siRNA knockdown with glycosylation readout","pmids":["28928140"],"confidence":"Medium","gaps":["Direct KCP2-SelT contact within the complex not mapped","KCP2 was a secondary subject of the study"]},{"year":2013,"claim":"Reported a candidate transient interaction with the Na+/Mg2+ exchanger SLC41A1, hinting at a possible role in client maturation.","evidence":"Split-ubiquitin yeast two-hybrid screen (not confirmed by mass spectrometry)","pmids":["23823179"],"confidence":"Low","gaps":["Single yeast two-hybrid screen not confirmed by orthogonal method","Proposed role in folding/maturation untested functionally"]},{"year":2026,"claim":"Extended KRTCAP2 to disease by showing it drives glioma malignant behaviors and associates with an immunosuppressive macrophage-rich microenvironment.","evidence":"Knockdown/overexpression in glioma cell lines with proliferation/migration/invasion assays and multiplex IHC for macrophage co-localization","pmids":["41676149"],"confidence":"Medium","gaps":["Mechanistic link between OST/glycosylation function and tumor phenotype not established","Macrophage association is correlative; causal signaling pathway undefined"]},{"year":null,"claim":"How KCP2's molecular role in STT3A-OST-Sec61 coupling mechanistically connects to its effects on γ-secretase/APP processing and to glioma progression remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No causal pathway linking glycosylation function to tumor phenotype","Substrate specificity determinants unknown","No structural model of the OST-Sec61 bridge"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,4]}],"complexes":["STT3A-containing oligosaccharyltransferase (OST) complex"],"partners":["STT3A","STT3B","OST48","DC2","SELENOT","SLC41A1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N6L1","full_name":"Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit KCP2","aliases":["Keratinocyte-associated protein 2","KCP-2"],"length_aa":136,"mass_kda":14.7,"function":"Subunit of STT3A-containing oligosaccharyl transferase (OST-A) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation (PubMed:22467853, PubMed:28860277). N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER) (PubMed:22467853, PubMed:28860277). Within the OST-A complex, acts as an adapter that anchors the OST-A complex to the Sec61 complex (PubMed:28860277). May be involved in N-glycosylation of APP (amyloid-beta precursor protein) (PubMed:21768116). Can modulate gamma-secretase cleavage of APP by enhancing endoprotelysis of PSEN1 (PubMed:21768116)","subcellular_location":"Endoplasmic reticulum; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q8N6L1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRTCAP2","classification":"Not Classified","n_dependent_lines":89,"n_total_lines":1208,"dependency_fraction":0.07367549668874172},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000163463","cell_line_id":"CID000179","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"DAD1","stoichiometry":10.0},{"gene":"DDOST","stoichiometry":10.0},{"gene":"RPN2","stoichiometry":10.0},{"gene":"RPN1","stoichiometry":10.0},{"gene":"MLEC","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2},{"gene":"STT3A","stoichiometry":0.2},{"gene":"TMPO","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000179","total_profiled":1310},"omim":[{"mim_id":"619029","title":"KERATINOCYTE-ASSOCIATED PROTEIN 2; KRTCAP2","url":"https://www.omim.org/entry/619029"},{"mim_id":"619023","title":"OLIGOSACCHARYLTRANSFERASE COMPLEX, NONCATALYTIC SUBUNIT; OSTC","url":"https://www.omim.org/entry/619023"},{"mim_id":"618932","title":"OLIGOSACCHARYLTRANSFERASE COMPLEX, SUBUNIT 4, NONCATALYTIC; OST4","url":"https://www.omim.org/entry/618932"},{"mim_id":"608605","title":"OLIGOSACCHARYLTRANSFERASE COMPLEX, CATALYTIC SUBUNIT STT3B; STT3B","url":"https://www.omim.org/entry/608605"},{"mim_id":"601134","title":"OLIGOSACCHARYLTRANSFERASE COMPLEX, CATALYTIC SUBUNIT STT3A; STT3A","url":"https://www.omim.org/entry/601134"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KRTCAP2"},"hgnc":{"alias_symbol":["KCP2"],"prev_symbol":[]},"alphafold":{"accession":"Q8N6L1","domains":[{"cath_id":"-","chopping":"4-118","consensus_level":"high","plddt":89.1143,"start":4,"end":118}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6L1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6L1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6L1-F1-predicted_aligned_error_v6.png","plddt_mean":82.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRTCAP2","jax_strain_url":"https://www.jax.org/strain/search?query=KRTCAP2"},"sequence":{"accession":"Q8N6L1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N6L1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N6L1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6L1"}},"corpus_meta":[{"pmid":"15835887","id":"PMC_15835887","title":"Proteomic analysis of mammalian oligosaccharyltransferase reveals multiple subcomplexes that contain Sec61, TRAP, and two potential new subunits.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15835887","citation_count":113,"is_preprint":false},{"pmid":"17337210","id":"PMC_17337210","title":"Transcriptome analysis of gills from the white shrimp Litopenaeus vannamei infected with White Spot Syndrome Virus.","date":"2007","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17337210","citation_count":85,"is_preprint":false},{"pmid":"22467853","id":"PMC_22467853","title":"The oligosaccharyltransferase subunits OST48, DAD1 and KCP2 function as ubiquitous and selective modulators of mammalian N-glycosylation.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22467853","citation_count":78,"is_preprint":false},{"pmid":"28928140","id":"PMC_28928140","title":"Selenoprotein T is a novel OST subunit that regulates UPR signaling and hormone secretion.","date":"2017","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/28928140","citation_count":51,"is_preprint":false},{"pmid":"28860277","id":"PMC_28860277","title":"DC2 and KCP2 mediate the interaction between the oligosaccharyltransferase and the ER translocon.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28860277","citation_count":43,"is_preprint":false},{"pmid":"22266900","id":"PMC_22266900","title":"Keratinocyte-associated protein 2 is a bona fide subunit of the mammalian oligosaccharyltransferase.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22266900","citation_count":30,"is_preprint":false},{"pmid":"37083227","id":"PMC_37083227","title":"Deciphering the Molecular Characteristics of Human Idiopathic Nonobstructive Azoospermia from the Perspective of Germ Cells.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37083227","citation_count":27,"is_preprint":false},{"pmid":"26492273","id":"PMC_26492273","title":"Aberrant MUC1-TRIM46-KRTCAP2 Chimeric RNAs in High-Grade Serous Ovarian Carcinoma.","date":"2015","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/26492273","citation_count":16,"is_preprint":false},{"pmid":"21768116","id":"PMC_21768116","title":"DC2 and keratinocyte-associated protein 2 (KCP2), subunits of the oligosaccharyltransferase complex, are regulators of the gamma-secretase-directed processing of amyloid precursor protein (APP).","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21768116","citation_count":15,"is_preprint":false},{"pmid":"36081994","id":"PMC_36081994","title":"Systematic review of gastric cancer-associated genetic variants, gene-based meta-analysis, and gene-level functional analysis to identify candidate genes for drug development.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36081994","citation_count":14,"is_preprint":false},{"pmid":"38831441","id":"PMC_38831441","title":"Single-cell and genome-wide Mendelian randomization identifies causative genes for gout.","date":"2024","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38831441","citation_count":12,"is_preprint":false},{"pmid":"37793074","id":"PMC_37793074","title":"Rational Redesign of Chitosanase to Enhance Thermostability and Catalytic Activity to Produce Chitooligosaccharides with a Relatively High Degree of Polymerization.","date":"2023","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37793074","citation_count":12,"is_preprint":false},{"pmid":"28324580","id":"PMC_28324580","title":"A statistical approach for the production of thermostable and alklophilic alpha-amylase from Bacillus amyloliquefaciens KCP2 under solid-state fermentation.","date":"2014","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/28324580","citation_count":11,"is_preprint":false},{"pmid":"37551622","id":"PMC_37551622","title":"A workflow to study mechanistic indicators for driver gene prediction with Moonlight.","date":"2023","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/37551622","citation_count":10,"is_preprint":false},{"pmid":"40229327","id":"PMC_40229327","title":"Multi-omics analysis identifies diagnostic circulating biomarkers and potential therapeutic targets, revealing IQGAP1 as an oncogene in gastric cancer.","date":"2025","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40229327","citation_count":9,"is_preprint":false},{"pmid":"23823179","id":"PMC_23823179","title":"Nature of SLC41A1 complexes: report on the split-ubiquitin yeast two hybrid assay.","date":"2013","source":"Magnesium research","url":"https://pubmed.ncbi.nlm.nih.gov/23823179","citation_count":8,"is_preprint":false},{"pmid":"39386830","id":"PMC_39386830","title":"Targeted metabolomics of muscle amino acid profles and hepatic transcriptomics analyses in grass carp (Ctenopharyngodon idellus) fed with broad beans.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39386830","citation_count":3,"is_preprint":false},{"pmid":"39161423","id":"PMC_39161423","title":"Mendelian randomization analysis identified potential genes pleiotropically associated with gout.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39161423","citation_count":2,"is_preprint":false},{"pmid":"35701113","id":"PMC_35701113","title":"[Exploring the association between de novo mutations and non-syndromic cleft lip with or without palate based on whole exome sequencing of case-parent trios].","date":"2022","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35701113","citation_count":1,"is_preprint":false},{"pmid":"26915194","id":"PMC_26915194","title":"[Irrigation scheduling with a 20 cm standard pan for drip-irrigated cucumber grown in solar greenhouse in the North China Plain].","date":"2015","source":"Ying yong sheng tai xue bao = The journal of applied ecology","url":"https://pubmed.ncbi.nlm.nih.gov/26915194","citation_count":1,"is_preprint":false},{"pmid":"41676149","id":"PMC_41676149","title":"KRTCAP2 accelerates malignant progression through modulating tumor cell function and M2 macrophage infiltration in glioma.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41676149","citation_count":0,"is_preprint":false},{"pmid":"42163732","id":"PMC_42163732","title":"Mendelian Randomization Analysis of the Relationship between Neurotransmitter-related Genes and Cancer: Insights from Multi-omics Data.","date":"2026","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42163732","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13609,"output_tokens":2200,"usd":0.036914,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9222,"output_tokens":2706,"usd":0.05688,"stage2_stop_reason":"end_turn"},"total_usd":0.093794,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"KCP2 (KRTCAP2), a 14 kDa protein, was co-purified with the mammalian oligosaccharyltransferase (OST) complex from solubilized, actively engaged ribosomes, identifying it as a potential new OST subunit with no previously known function.\",\n      \"method\": \"2D Blue Native PAGE/SDS-PAGE and mass spectrometry co-purification from ribosome translocon complexes\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry-based co-purification is rigorous but single lab; no functional follow-up in this paper\",\n      \"pmids\": [\"15835887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human KCP2 is an integral membrane protein with three transmembrane spans resulting from alternative initiation of translation, localizes to the endoplasmic reticulum via a functional KKxx retrieval signal at its cytosolic C-terminus, and assembles into a ~500 kDa OST complex predominantly containing the catalytic STT3A isoform; co-immunoprecipitation confirmed robust physical interaction with STT3A and weaker associations with STT3B and OST48.\",\n      \"method\": \"Alternative translation initiation characterization, ER localization by immunofluorescence, native gel analysis, co-immunoprecipitation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (topology mapping, localization, native gel, Co-IP) in a single focused mechanistic study\",\n      \"pmids\": [\"22266900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KCP2 depletion causes substrate-specific hypoglycosylation (not global OST disruption) and leads to accumulation of a novel STT3A-containing OST subcomplex, suggesting KCP2 selectively enhances OST-dependent processing of specific co-translational substrates of STT3A-containing complexes; by contrast, OST48 and DAD1 knockdown globally destabilizes both STT3A- and STT3B-containing complexes.\",\n      \"method\": \"siRNA knockdown, glycosylation assays, native gel electrophoresis, subunit-specific depletion analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, glycosylation assay, native gel) in single focused mechanistic study; distinct KCP2 phenotype from other OST subunits clearly established\",\n      \"pmids\": [\"22467853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KCP2 (together with DC2) depletion affects APP (amyloid precursor protein) processing in a substrate-specific manner: knockdown leads to accumulation of C-terminal fragments C99 and C83 and reduced full-length mature APP, and specifically reduces the active PS1 fragment of the γ-secretase complex blocking Aβ production; conversely, overexpression of KCP2 increases the active γ-secretase complex and stimulates Aβ production, indicating KCP2 interacts with and modulates the γ-secretase pathway.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot analysis of APP processing intermediates, γ-secretase activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with specific mechanistic readouts, single lab, two orthogonal perturbations\",\n      \"pmids\": [\"21768116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DC2 and KCP2 mediate the physical interaction between the STT3A-containing OST complex and the Sec61 protein translocation channel; loss of DC2 causes a co-translational N-glycosylation defect mimicking the STT3A phenotype, while DC2- and KCP2-deficient STT3A complexes remain stable and enzymatically active, demonstrating these subunits are specifically required for translocon association rather than for OST catalytic activity.\",\n      \"method\": \"CRISPR/genome-edited human cell lines deficient in DC2 or KCP2, biochemical fractionation, co-immunoprecipitation, deletion mutagenesis of DC2 functional motifs, N-glycosylation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetically modified human cells with multiple orthogonal biochemical approaches plus mutagenesis; directly establishes mechanism\",\n      \"pmids\": [\"28860277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KCP2 was identified as a binding partner of selenoprotein T (SelT) in a yeast membrane protein interaction screen, and SelT interacts with KCP2 and other subunits of the A-type OST complex; SelT knockdown depletes A-type OST subunits including KCP2 and causes POMC N-glycosylation defects, positioning SelT as a novel subunit required for A-type OST complex integrity.\",\n      \"method\": \"Split-ubiquitin yeast two-hybrid screen, co-immunoprecipitation, SelT siRNA knockdown with N-glycosylation readout\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus Co-IP plus functional knockdown; single lab; KCP2 role here is as interacting partner rather than primary subject\",\n      \"pmids\": [\"28928140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KCP2 was identified as a binding partner of the Na+/Mg2+ exchanger SLC41A1 in a split-ubiquitin yeast two-hybrid screen; the interaction was categorized as forming a transient rather than stable complex, and KCP2 was proposed to contribute to SLC41A1 production, folding, or maturation in the ER.\",\n      \"method\": \"Split-ubiquitin yeast two-hybrid assay (polyton — appeared more than once in screen); interaction not confirmed by mass spectrometry\",\n      \"journal\": \"Magnesium research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid screen, not confirmed by orthogonal method, single lab\",\n      \"pmids\": [\"23823179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KRTCAP2 depletion in glioma cells inhibited proliferation, migration, and invasion, while overexpression promoted these malignant behaviors; KRTCAP2 expression was positively associated with infiltration of CD68+ and CD163+ tumor-associated macrophages, indicating a role in promoting an immunosuppressive tumor microenvironment.\",\n      \"method\": \"siRNA/shRNA knockdown and overexpression in glioma cell lines, in vitro functional assays (proliferation, migration, invasion), multiplex immunohistochemistry for immune cell co-localization, drug sensitivity (apoptosis) assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vitro loss- and gain-of-function with defined cellular phenotypes and immune cell association; single lab, no mechanistic pathway placement beyond N-glycosylation inference\",\n      \"pmids\": [\"41676149\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRTCAP2 (KCP2) is a non-catalytic integral membrane subunit of the mammalian STT3A-containing oligosaccharyltransferase (OST) complex in the ER, where it localizes via a KKxx retrieval signal; together with DC2, it physically bridges the STT3A-OST complex to the Sec61 protein translocation channel to enable co-translational N-glycosylation of specific substrates, while also modulating γ-secretase activity and APP processing, and promoting glioma cell proliferation, migration, and immunosuppression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KRTCAP2 (KCP2) is a small, non-catalytic integral membrane subunit of the mammalian STT3A-containing oligosaccharyltransferase (OST) complex that supports co-translational N-glycosylation in the endoplasmic reticulum [#0, #1]. It is an integral membrane protein with three transmembrane spans generated by alternative translation initiation, and it is retained in the ER via a functional KKxx retrieval signal at its cytosolic C-terminus, assembling into a ~500 kDa complex built around the catalytic STT3A isoform with which it interacts robustly [#1]. Rather than contributing to OST catalysis, KCP2 together with DC2 physically bridges the STT3A-OST complex to the Sec61 translocation channel, and KCP2-deficient complexes remain stable and enzymatically active [#4]; consistent with this dedicated role, its loss produces substrate-specific hypoglycosylation and accumulation of an STT3A-containing subcomplex rather than the global OST destabilization seen when core subunits are depleted [#2]. KCP2 also modulates γ-secretase activity and APP processing, with depletion causing accumulation of the C99/C83 fragments and reduced Aβ production and overexpression stimulating active γ-secretase and Aβ generation [#3]. In glioma cells, KRTCAP2 promotes proliferation, migration, and invasion and is associated with tumor-associated macrophage infiltration and an immunosuppressive microenvironment [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that an uncharacterized 14 kDa protein physically associates with the translation/translocation machinery, raising the possibility of a new OST subunit.\",\n      \"evidence\": \"Blue Native/SDS-PAGE and mass spectrometry co-purification from ribosome-translocon complexes\",\n      \"pmids\": [\"15835887\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No functional role assigned\", \"Membership in OST not yet confirmed by orthogonal methods\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked KCP2 to a specific cellular pathway by showing it modulates APP processing and γ-secretase activity, indicating substrate-specific regulatory influence.\",\n      \"evidence\": \"siRNA knockdown, overexpression, and Western analysis of APP intermediates plus γ-secretase activity assays\",\n      \"pmids\": [\"21768116\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct physical interaction with γ-secretase components not resolved\", \"Mechanistic link to its OST/glycosylation function not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined KCP2 topology, ER localization, and complex membership, establishing it as a bona fide subunit of the STT3A-containing OST.\",\n      \"evidence\": \"Alternative initiation mapping, immunofluorescence, native gel analysis, and co-immunoprecipitation\",\n      \"pmids\": [\"22266900\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional contribution to glycosylation not yet defined\", \"Basis for STT3A preference unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Distinguished KCP2 from core OST subunits by showing its loss causes substrate-specific hypoglycosylation and a stable subcomplex rather than global complex collapse.\",\n      \"evidence\": \"siRNA knockdown with glycosylation assays, native gel electrophoresis, and subunit-specific depletion comparison\",\n      \"pmids\": [\"22467853\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Identity of the affected substrate set not fully defined\", \"Mechanism of selectivity unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the functional role by demonstrating that KCP2 and DC2 tether the STT3A-OST to the Sec61 channel and are required for translocon association, not catalysis.\",\n      \"evidence\": \"CRISPR-edited human cells, biochemical fractionation, Co-IP, deletion mutagenesis, and N-glycosylation assays\",\n      \"pmids\": [\"28860277\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural details of the OST-Sec61 bridge not defined\", \"Relative contributions of KCP2 versus DC2 not dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed KCP2 within the broader A-type OST interactome by identifying SelT as a partner whose loss depletes KCP2 and impairs N-glycosylation.\",\n      \"evidence\": \"Split-ubiquitin yeast two-hybrid screen, Co-IP, and SelT siRNA knockdown with glycosylation readout\",\n      \"pmids\": [\"28928140\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct KCP2-SelT contact within the complex not mapped\", \"KCP2 was a secondary subject of the study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reported a candidate transient interaction with the Na+/Mg2+ exchanger SLC41A1, hinting at a possible role in client maturation.\",\n      \"evidence\": \"Split-ubiquitin yeast two-hybrid screen (not confirmed by mass spectrometry)\",\n      \"pmids\": [\"23823179\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single yeast two-hybrid screen not confirmed by orthogonal method\", \"Proposed role in folding/maturation untested functionally\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended KRTCAP2 to disease by showing it drives glioma malignant behaviors and associates with an immunosuppressive macrophage-rich microenvironment.\",\n      \"evidence\": \"Knockdown/overexpression in glioma cell lines with proliferation/migration/invasion assays and multiplex IHC for macrophage co-localization\",\n      \"pmids\": [\"41676149\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic link between OST/glycosylation function and tumor phenotype not established\", \"Macrophage association is correlative; causal signaling pathway undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KCP2's molecular role in STT3A-OST-Sec61 coupling mechanistically connects to its effects on γ-secretase/APP processing and to glioma progression remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No causal pathway linking glycosylation function to tumor phenotype\", \"Substrate specificity determinants unknown\", \"No structural model of the OST-Sec61 bridge\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"complexes\": [\"STT3A-containing oligosaccharyltransferase (OST) complex\"],\n    \"partners\": [\"STT3A\", \"STT3B\", \"OST48\", \"DC2\", \"SELENOT\", \"SLC41A1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}