{"gene":"TAP2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1994,"finding":"Both TAP1 and TAP2 subunits are photolabeled by peptide photoprobes, indicating that elements of both subunits compose the peptide-recognition site. Efficient formation of the peptide-binding site requires coexpression of TAP1 and TAP2, supporting the notion that TAP functions as a heterodimer. MHC class I/beta2m dimers associate with TAP1 but are not detectable with TAP2 alone, suggesting that the TAP1 chain is the primary site of MHC class I/beta2m interaction.","method":"TAP photoaffinity labeling with photopeptide analogues; transfectant cell lines expressing TAP1 and TAP2 individually and together; peptide translocation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro assays (photoaffinity labeling, translocation assays, co-expression studies) in a single rigorous study","pmids":["7809108"],"is_preprint":false},{"year":1996,"finding":"Peptide transport specificity with regard to the C-terminal amino acid of transported peptides is mainly determined by TAP2. The N-terminal region (residues 1–361) of TAP2 critically controls selective transport of peptides with C-terminal positively charged residues. A single point mutation in human TAP2 (374A→D) drastically alters the transport pattern, demonstrating that single residues in TAP2 control peptide selectivity.","method":"Interspecies TAP hybrid construction; point mutagenesis of hTAP2; expression in Sf9 insect cells and TAP-deficient T2 cells; peptide transport assays with 20 C-terminal variants","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in insect cells plus mutagenesis with functional transport assay, multiple orthogonal approaches in one study","pmids":["8765016"],"is_preprint":false},{"year":2000,"finding":"Walker A lysine mutation in TAP2 (K509M) does not significantly impair nucleotide binding relative to wild-type TAP2, unlike the equivalent TAP1 mutation. TAP1·TAP2(K509M) complexes show undetectable peptide translocation, while TAP1(K544M)·TAP2 complexes retain low-level translocation, indicating that both NBDs must be functional for efficient peptide translocation and suggesting distinct roles for TAP1 and TAP2 NBDs in a single translocation cycle.","method":"Site-directed mutagenesis of Walker A motifs; expression in insect cells; nucleotide binding assays; fluorescence quenching peptide binding assays; peptide translocation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in insect cells with mutagenesis plus multiple functional readouts (nucleotide binding, peptide binding, translocation) in one rigorous study","pmids":["11099504"],"is_preprint":false},{"year":2002,"finding":"Tapasin binds to both TAP1 and TAP2 via their membrane-spanning regions; interactions with the nucleotide binding domain alone are not observed. Tapasin is not required for high-affinity peptide binding to TAP1·TAP2 complexes and slightly reduces peptide-binding affinity. However, tapasin and nucleotides together stabilize the peptide-binding site against inactivation at near-physiological temperatures, enhancing structural stability of both TAP subunits.","method":"Tapasin co-expression with TAP variants in insect cells; truncation and chimera constructs; thermal stability assays; peptide binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with defined constructs plus multiple functional readouts (binding, thermal stability) in one study","pmids":["12213826"],"is_preprint":false},{"year":2006,"finding":"TAP2 catalytic site residues Glu632 (Walker B) and His661 (switch region) are critical for peptide translocation and MHC class I surface expression. Alterations at these residues significantly reduced TAP activity, whereas equivalent mutations in the degenerate TAP1 catalytic site (Asp668, Gln701) had only small effects. The TAP2 nucleotide-binding site (second site) is therefore the main catalytically active site driving peptide transport, consistent with an asymmetric one-main-active-site mechanism.","method":"Site-directed mutagenesis of catalytic residues in TAP1 and TAP2; expression in TAP-deficient cells; peptide translocation assays; MHC class I surface expression assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of both catalytic sites combined with two orthogonal functional readouts in one rigorous study","pmids":["17068338"],"is_preprint":false},{"year":2005,"finding":"Truncation of the N-terminal domain of TAP2 (but not TAP1) produces peptide-loading complexes that fail to generate stable MHC class I–peptide complexes, correlating with substantially reduced recruitment of accessory chaperones into the PLC. This identifies the tapasin-docking site on TAP2 as critical for the functional integrity of the MHC class I peptide-loading complex.","method":"Expression of N-terminally truncated TAP variants; co-immunoprecipitation of PLC components; MHC class I surface expression assays; functional peptide-loading assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean domain-deletion approach with multiple orthogonal readouts (co-IP, surface expression, peptide loading) in one study","pmids":["16210614"],"is_preprint":false},{"year":2005,"finding":"N-terminal domains of both TAP1 and TAP2 (defined by proteolytic cleavage sites at residues 131 of TAP1 and 88 of TAP2) are dispensable for peptide and nucleotide binding and support peptide translocation (albeit with reduced efficiency), but are required for tapasin binding and for the tapasin-mediated enhancement of MHC class I peptide loading.","method":"Expression and purification of human TAP1/TAP2 complexes from insect cells; limited proteolysis; N-terminal truncation variants; peptide binding and translocation assays; insect cell-based reconstitution of MHC class I loading pathway; tapasin binding assays","journal":"Immunology and cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in insect cells with defined truncations, multiple orthogonal assays (binding, translocation, MHC loading) in one study","pmids":["16174096"],"is_preprint":false},{"year":2006,"finding":"TAP2 is highly unstable when expressed in isolation and requires heterodimerization with TAP1 for stable expression. Functional TAP biogenesis requires assembly of pre-existing TAP1 with newly synthesized TAP2 (but not vice versa). The core transmembrane domain of TAP2 is necessary and sufficient for functional complex formation with pre-existing TAP1.","method":"In vitro expression system; pulse-chase/stability assays; domain truncation and chimera constructs; functional peptide transport assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined domain constructs and multiple functional readouts including translocation assays","pmids":["16624807"],"is_preprint":false},{"year":2007,"finding":"Multiple residues in the transmembrane domain (TMD) and ER-luminal connecting peptide (CP) of tapasin are required to stabilize the TAP2 subunit. A conserved Lys in the center of the tapasin TMD plus four predicted helix-face neighbors must be mutated together to abolish TAP2 stabilization. A highly conserved Glu in the ER-luminal CP also strongly contributes to TAP2 stabilization. Loss of TAP2 stabilization impairs MHC class I surface expression.","method":"Mutational analysis of tapasin TMD and CP; transfection of tapasin-deficient cells; Western blot quantification of TAP2 protein levels; MHC class I surface expression assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — detailed systematic mutagenesis with clean tapasin-deficient cell background and multiple orthogonal readouts","pmids":["17244610"],"is_preprint":false},{"year":2002,"finding":"Individual TAP2 polypeptide subunits, when expressed alone, interact with multiple MHC class I alleles (HLA-A2, -B51, -A*2501, -B*2704, -B*3501, -B*4402) and can form peptide-loading complexes. TAP2, but not TAP1, has the ability to form homodimers both in whole cells and in detergent lysates, as demonstrated by chemical cross-linking.","method":"Immunoprecipitation of individually expressed TAP subunits in TAP-deficient T2 cells; recombinant vaccinia virus expression of HLA alleles; chemical cross-linking","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP/cross-linking approach, single lab, but multiple HLA alleles tested providing convergent evidence","pmids":["12047747"],"is_preprint":false},{"year":1997,"finding":"MHC class I molecules interact with both TAP1 and TAP2 subunits. In TAP-deficient T2 cells expressing rat TAP2 alone, MHC class I molecules associate with TAP2, and this interaction also involves calreticulin and tapasin, indicating that the interaction of MHC class I with TAP is not exclusive to TAP1.","method":"Immunoprecipitation from TAP-deficient T2 cells transfected with individual rat TAP subunits","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP experiment in a clean TAP-deficient background, single lab","pmids":["9368636"],"is_preprint":false},{"year":2001,"finding":"EBV latent membrane protein 1 (LMP-1) induces TAP2 expression via IRF-7 as a secondary mediator: LMP-1 stimulates IRF-7 expression, facilitates IRF-7 phosphorylation and nuclear translocation, and activated IRF-7 binds the TAP2 promoter ISRE element to activate TAP2 transcription. Only IRF-7A splice variant (not other isoforms) activates TAP2. TAP2 induction by LMP-1 requires an intact ISRE in the TAP2 promoter.","method":"Endogenous TAP2 induction assays in Burkitt's lymphoma cell lines; ectopic IRF-7 expression; TAP2 promoter reporter assays; formaldehyde cross-linking ChIP; gel mobility shift assay; cell complementation experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay, ChIP, EMSA, cell complementation) in one study establishing mechanistic pathway","pmids":["11119603"],"is_preprint":false},{"year":1993,"finding":"In the murine TAP2-defective RMA-S cell line, antigen presentation of Sendai virus via MHC class I is possible but requires 2–3 h longer incubation and ~10× higher virus dose compared to wild-type cells. Transfection of murine TAP1/TAP2 genes into RMA-S cells fully restores Sendai virus antigen presentation, confirming that TAP2 is required for efficient endogenous antigen presentation.","method":"CTL killing assays with TAP2-defective RMA-S cells vs. parental RMA; TAP1/TAP2 gene transfection rescue; brefeldin A sensitivity assay","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic rescue (transfection) with functional CTL readout, single lab","pmids":["8393798"],"is_preprint":false},{"year":1994,"finding":"Expression of class Ib Qa-2 molecules (both GPI-anchored and soluble forms) requires functional TAP2: in TAP2-defective RMA-S cells, Qa-2 molecules behave as empty heterodimers unstable at 37°C but stabilized at 26°C, similar to class Ia molecules. A minor population of heat-resistant Qa-2 in RMA-S suggests a secondary TAP-independent peptide loading pathway.","method":"Temperature-shift stability assays; peptide loading assays; immunoprecipitation from TAP2-defective RMA-S cells vs. wild-type","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean TAP2-null genetic background with functional stability and peptide-loading readouts, single lab","pmids":["8189046"],"is_preprint":false},{"year":1995,"finding":"TL (thymus-leukemia antigen), a class Ib MHC molecule, is expressed efficiently at the cell surface in the absence of functional TAP2 in RMA-S cells, unlike most MHC class I molecules. Surface TL in TAP2-deficient cells is associated with beta2m but heavy chains are cleaved to a ~38 kDa fragment, suggesting altered conformation when loaded without TAP2-dependent peptides.","method":"Expression of TL constructs in RMA and RMA-S cells; immunoprecipitation; SDS-PAGE; surface expression assays; temperature-shift assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean TAP2-null genetic background with multiple biochemical readouts, single lab","pmids":["7737270"],"is_preprint":false},{"year":2003,"finding":"Cysteine-less TAP1 and TAP2 subunits (all 19 cysteines replaced by de novo gene synthesis) are functional with respect to ATP-dependent peptide transport and inhibition by viral TAP inhibitor ICP47, and restore MHC class I maturation and trafficking, demonstrating that none of the cysteine residues in TAP1 or TAP2 are individually essential for core transport function.","method":"De novo gene synthesis of cysteine-less TAP1/TAP2; expression in TAP-deficient human fibroblasts; peptide transport assays; ICP47 inhibition assay; MHC class I surface expression assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstitution with functional readout (transport, MHC expression), single lab, single paper","pmids":["12505156"],"is_preprint":false},{"year":2009,"finding":"A point mutation in mouse TAP2 (Thr293Pro) causes severe reduction in TAP2 protein without affecting mRNA levels, and also decreases TAP1 protein levels, demonstrating a role for mouse TAP2 in stabilizing TAP1 protein expression. Mice with defective TAP2 show very low MHC class I surface expression and few CD8+ T cells.","method":"ENU mutagenesis screen; genotyping; mRNA and protein expression analysis (Western blot); flow cytometry for MHC class I and CD8+ T cells","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — point-mutant mouse model with defined molecular lesion and multiple cellular readouts, single lab","pmids":["19721454"],"is_preprint":false},{"year":2014,"finding":"Natural polymorphisms in rat Tap2 influence the peptide repertoire loaded onto MHC class I molecules, which in turn affects negative selection and CD4:CD8 lineage commitment of thymocytes. A recombination between RT1-A (MHC class I) and Tap2 alleles revealed that the restricted peptide repertoire conferred by a Tap2 variant leads to reduced negative selection of CD8 single-positive thymocytes.","method":"QTL mapping in outbred Heterogeneous Stock rats; MHC-recombinant congenic strain panel; flow cytometry for thymocyte subsets and MHC expression; genetic epistasis analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by genetic recombinant congenic panel with defined cellular phenotype, replicated across multiple strains","pmids":["24586191"],"is_preprint":false},{"year":2007,"finding":"TAP2 coding SNP alleles influence differential splicing into two isoforms with alternative C-terminals that have distinct peptide selectivities. The G (Ala) allele at codon 665 is more than twice as abundant in isoform NM_000544, while isoform NM_018833 is derived almost exclusively from chromosomes carrying the A (Thr) allele, providing a plausible functional mechanism by which coding TAP2 polymorphisms may indirectly alter peptide selectivity.","method":"Allele-specific relative isoform quantification in heterozygous lymphoblastoid cell lines; transmission disequilibrium test in type 1 diabetes families","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct allele-isoform quantification in primary cells with two orthogonal analyses, single lab","pmids":["17192492"],"is_preprint":false},{"year":1992,"finding":"Transfection of the Tap-2 gene into RMA-S (TAP2-defective) cells restores surface expression of QA-1b class Ib molecules and rescues recognition by Qdm-dependent (but not all Qdm-independent) anti-Qa-1 CTL, demonstrating that TAP2 is required for loading of specific peptides onto Qa-1b and that Qdm encodes a peptide whose surface expression depends on the TAP transporter.","method":"Tap-2 gene transfection into RMA-S cells; CTL killing assays with Qdm-dependent and independent clones","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic rescue with functional CTL readout, single lab","pmids":["1460275"],"is_preprint":false},{"year":2018,"finding":"Naturally occurring TAP1 and TAP2 polymorphisms have no or limited effect on peptide transport or MHC class I surface expression. Herpesvirus-encoded TAP inhibitors (US6, ICP47, BNLF2a) inhibit a broad spectrum of TAP1/TAP2 variant combinations, indicating that viral immune evasion targets TAP in a polymorphism-independent manner.","method":"Expression of TAP1/TAP2 variant combinations; peptide transport assays; MHC class I surface expression assays; inhibition by viral TAP inhibitors","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transport assays across multiple variant combinations, single lab, orthogonal readouts","pmids":["29879547"],"is_preprint":false}],"current_model":"TAP2 is an essential subunit of the heterodimeric ABC transporter TAP1/TAP2 that translocates antigenic peptides from the cytosol into the ER for MHC class I loading; TAP2 contributes to the shared peptide-recognition site, is the primary determinant of C-terminal peptide specificity via its N-terminal transmembrane region, harbors the main catalytically active nucleotide-binding site (Glu632/His661) driving transport, requires tapasin binding via its N-terminal domain and transmembrane region for PLC integrity and MHC class I loading efficiency, is stabilized by heterodimerization with TAP1 (biogenesis requires pre-existing TAP1 to assemble with newly synthesized TAP2), and is transcriptionally regulated by the IRF-7/LMP-1 axis through an ISRE element in its promoter."},"narrative":{"mechanistic_narrative":"TAP2 is an essential subunit of the heterodimeric ABC transporter TAP1/TAP2, which translocates antigenic peptides from the cytosol into the ER for loading onto MHC class I molecules and is required for efficient endogenous antigen presentation [PMID:7809108, PMID:8393798]. TAP functions only as a heterodimer: both subunits contribute elements of the shared peptide-recognition site, and TAP2 is intrinsically unstable in isolation, requiring assembly of newly synthesized TAP2 with pre-existing TAP1 — a process directed by its core transmembrane domain — for stable expression [PMID:7809108, PMID:16624807]. TAP2 is the primary determinant of C-terminal peptide selectivity, with its N-terminal region (residues 1–361) controlling transport of peptides bearing C-terminal charged residues and single point substitutions (e.g. 374A→D) drastically reshaping the transport pattern [PMID:8765016]. Within the asymmetric nucleotide-binding architecture, the TAP2 catalytic site (Glu632 Walker B, His661 switch region) constitutes the main catalytically active site driving transport, whereas the degenerate TAP1 site contributes little, consistent with a one-main-active-site mechanism; nonetheless efficient translocation requires both NBDs to be functional [PMID:11099504, PMID:17068338]. TAP2's N-terminal domain and transmembrane region provide the tapasin-docking site essential for recruiting accessory chaperones into the peptide-loading complex and for stable MHC class I–peptide assembly, and tapasin together with nucleotides stabilizes the peptide-binding site against thermal inactivation [PMID:12213826, PMID:16210614, PMID:16174096]. TAP2 is transcriptionally induced by the EBV LMP-1/IRF-7 axis, with activated IRF-7A binding an ISRE element in the TAP2 promoter [PMID:11119603]. Natural TAP2 polymorphisms and alternative splicing shape the loaded peptide repertoire, with downstream consequences for thymocyte selection [PMID:24586191, PMID:17192492].","teleology":[{"year":1992,"claim":"Established that TAP2 is functionally required for surface loading of specific TAP-dependent peptides, linking the transporter to a defined antigen repertoire.","evidence":"Tap-2 gene transfection rescue of RMA-S cells with Qdm-dependent CTL killing readout","pmids":["1460275"],"confidence":"Medium","gaps":["Did not define which peptide features depend on TAP2 versus TAP1","No biochemical reconstitution of transport"]},{"year":1993,"claim":"Quantified the requirement for TAP2 in endogenous antigen presentation, showing it is needed for efficient (not absolute) MHC class I-restricted presentation.","evidence":"CTL killing assays in TAP2-defective RMA-S cells with TAP1/TAP2 transfection rescue","pmids":["8393798"],"confidence":"Medium","gaps":["Residual presentation indicates a TAP-independent pathway not characterized","Single virus model"]},{"year":1994,"claim":"Resolved that the peptide-recognition site is composed of elements from both subunits and that TAP must function as a heterodimer, clarifying subunit roles in substrate binding.","evidence":"Photoaffinity labeling, co-expression studies, and translocation assays in transfectant cell lines","pmids":["7809108"],"confidence":"High","gaps":["Did not resolve residue-level contacts of each subunit","Relative contribution of each subunit to specificity not quantified"]},{"year":1994,"claim":"Extended the TAP2 requirement to class Ib molecules, showing Qa-2 stability depends on TAP2-mediated peptide loading.","evidence":"Temperature-shift stability and peptide-loading assays in TAP2-defective RMA-S cells","pmids":["8189046"],"confidence":"Medium","gaps":["Nature of the minor TAP-independent loading pathway unresolved","Single class Ib molecule type"]},{"year":1995,"claim":"Demonstrated heterogeneity in TAP2 dependence among class Ib molecules, with TL reaching the surface without functional TAP2.","evidence":"Immunoprecipitation and surface expression of TL in RMA versus RMA-S cells","pmids":["7737270"],"confidence":"Medium","gaps":["Mechanism of TAP2-independent TL surface delivery not defined","Functional consequence of heavy-chain cleavage unclear"]},{"year":1996,"claim":"Localized C-terminal peptide selectivity primarily to TAP2 and to single residues in its N-terminal region, defining the structural basis of substrate discrimination.","evidence":"Interspecies TAP hybrids and point mutagenesis of hTAP2 with peptide transport assays in insect and T2 cells","pmids":["8765016"],"confidence":"High","gaps":["Structural mechanism by which residue 374 alters specificity not resolved","Did not map full set of selectivity-determining residues"]},{"year":1997,"claim":"Showed MHC class I can associate with TAP2 (with calreticulin and tapasin), establishing that the loading complex contact is not exclusive to TAP1.","evidence":"Immunoprecipitation from T2 cells transfected with individual rat TAP subunits","pmids":["9368636"],"confidence":"Medium","gaps":["Single Co-IP approach without reciprocal validation","Physiological relevance of TAP2-alone association unclear"]},{"year":2000,"claim":"Distinguished the functional roles of the two NBDs, showing both must be functional for efficient translocation but with asymmetric behavior between TAP1 and TAP2 Walker A sites.","evidence":"Walker A mutagenesis with nucleotide-binding, peptide-binding, and translocation assays in insect cells","pmids":["11099504"],"confidence":"High","gaps":["Precise ordering of NBD events in a cycle not defined","Did not assign catalytic versus regulatory roles definitively"]},{"year":2002,"claim":"Mapped the tapasin interaction to the membrane-spanning regions of both subunits and defined tapasin's role in thermal stabilization rather than peptide affinity.","evidence":"Tapasin co-expression with TAP truncation/chimera constructs, thermal stability and peptide binding assays in insect cells","pmids":["12213826"],"confidence":"High","gaps":["Residue-level tapasin contacts on TAP2 not yet defined","Did not address PLC chaperone recruitment"]},{"year":2002,"claim":"Revealed that TAP2, unlike TAP1, can homodimerize and individually engage multiple MHC class I alleles, indicating subunit-specific assembly properties.","evidence":"Immunoprecipitation and chemical cross-linking of individually expressed subunits in T2 cells","pmids":["12047747"],"confidence":"Medium","gaps":["Functional relevance of TAP2 homodimers in vivo unknown","Single lab, single approach"]},{"year":2005,"claim":"Identified the TAP2 N-terminal domain as critical for PLC integrity and chaperone recruitment, separating this role from core transport.","evidence":"N-terminal truncation variants with co-IP of PLC components and MHC class I surface/peptide-loading assays","pmids":["16210614","16174096"],"confidence":"High","gaps":["Identity of all recruited accessory chaperones not fully enumerated","Structural basis of N-terminal docking not resolved"]},{"year":2006,"claim":"Defined the TAP2 catalytic site (Glu632, His661) as the main catalytically active site driving transport, establishing an asymmetric one-main-active-site mechanism.","evidence":"Systematic catalytic-residue mutagenesis of both subunits with translocation and MHC class I surface assays","pmids":["17068338"],"confidence":"High","gaps":["Structural transition states not resolved","Role of degenerate TAP1 site beyond minor contribution unclear"]},{"year":2006,"claim":"Established that TAP2 biogenesis requires heterodimerization with pre-existing TAP1, with the core transmembrane domain sufficient for assembly.","evidence":"Stability/pulse-chase and domain-truncation constructs with functional transport assays","pmids":["16624807"],"confidence":"High","gaps":["Chaperones governing the ordered assembly not identified","Folding intermediates not characterized"]},{"year":2001,"claim":"Defined transcriptional control of TAP2 via the EBV LMP-1/IRF-7 axis acting on a promoter ISRE element.","evidence":"TAP2 promoter reporter assays, ChIP, EMSA, and IRF-7 complementation in lymphoma cell lines","pmids":["11119603"],"confidence":"High","gaps":["Other physiological transcriptional regulators of TAP2 not addressed","In vivo relevance during EBV infection not tested"]},{"year":2007,"claim":"Showed tapasin TMD and ER-luminal residues stabilize TAP2 protein, linking tapasin docking to subunit stability and MHC class I expression.","evidence":"Systematic tapasin TMD/CP mutagenesis in tapasin-deficient cells with TAP2 Western blot and MHC class I surface assays","pmids":["17244610"],"confidence":"High","gaps":["Mechanism of stabilization (folding versus degradation protection) not resolved"]},{"year":2007,"claim":"Linked TAP2 coding SNPs to differential isoform splicing with distinct peptide selectivities, providing a mechanism for polymorphism-driven repertoire variation.","evidence":"Allele-specific isoform quantification in heterozygous lymphoblastoid cells and TDT in type 1 diabetes families","pmids":["17192492"],"confidence":"Medium","gaps":["Direct functional consequence on peptide loading not measured","Disease association correlative"]},{"year":2009,"claim":"Demonstrated in vivo that TAP2 stabilizes TAP1 protein and is required for normal MHC class I expression and CD8+ T cell numbers.","evidence":"ENU mutant mouse (Thr293Pro) with mRNA/protein analysis and flow cytometry","pmids":["19721454"],"confidence":"Medium","gaps":["Mechanism of reciprocal TAP1 stabilization not defined","Single point lesion"]},{"year":2003,"claim":"Showed all cysteine residues are dispensable for core TAP transport function and viral inhibitor sensitivity.","evidence":"Cysteine-less TAP1/TAP2 de novo synthesis with transport, ICP47 inhibition, and MHC class I assays","pmids":["12505156"],"confidence":"Medium","gaps":["Single lab, single study","Subtle effects on stability or kinetics not excluded"]},{"year":2014,"claim":"Connected TAP2 polymorphism to the loaded peptide repertoire and downstream thymocyte negative selection and lineage commitment.","evidence":"QTL mapping and MHC-recombinant congenic rat panel with thymocyte flow cytometry and epistasis analysis","pmids":["24586191"],"confidence":"Medium","gaps":["Specific peptides driving altered selection not identified","Rat-specific allelic context"]},{"year":2018,"claim":"Established that natural TAP2 polymorphisms have limited functional impact and that viral inhibitors target TAP in a polymorphism-independent manner.","evidence":"Peptide transport and MHC class I assays across TAP1/TAP2 variant combinations with viral inhibitor testing","pmids":["29879547"],"confidence":"Medium","gaps":["Did not address rare or disease-associated variants in depth","Single lab"]},{"year":null,"claim":"How the asymmetric NBD cycle is coupled mechanically to peptide translocation across the membrane, and the structural basis of TAP2 C-terminal selectivity, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the translocation cycle in the timeline","Residue-level selectivity determinants beyond residue 374 not mapped","Full PLC architecture around TAP2 not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,4,12]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,5,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,12]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,2,4]}],"complexes":["TAP1/TAP2 transporter","MHC class I peptide-loading complex (PLC)"],"partners":["TAP1","TAPASIN","CALRETICULIN","MHC CLASS I HEAVY CHAIN","IRF-7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q03519","full_name":"Antigen peptide transporter 2","aliases":["ATP-binding cassette sub-family B member 3","Peptide supply factor 2","Peptide transporter PSF2","PSF-2","Peptide transporter TAP2","Peptide transporter involved in antigen processing 2","Really interesting new gene 11 protein","RING11"],"length_aa":686,"mass_kda":75.7,"function":"ABC transporter associated with antigen processing. In complex with TAP1 mediates unidirectional translocation of peptide antigens from cytosol to endoplasmic reticulum (ER) for loading onto MHC class I (MHCI) molecules (PubMed:25377891, PubMed:25656091). Uses the chemical energy of ATP to export peptides against the concentration gradient (PubMed:25377891). During the transport cycle alternates between 'inward-facing' state with peptide binding site facing the cytosol to 'outward-facing' state with peptide binding site facing the ER lumen. Peptide antigen binding to ATP-loaded TAP1-TAP2 induces a switch to hydrolysis-competent 'outward-facing' conformation ready for peptide loading onto nascent MHCI molecules. Subsequently ATP hydrolysis resets the transporter to the 'inward facing' state for a new cycle (PubMed:11274390, PubMed:25377891, PubMed:25656091). Typically transports intracellular peptide antigens of 8 to 13 amino acids that arise from cytosolic proteolysis via IFNG-induced immunoproteasome. Binds peptides with free N- and C-termini, the first three and the C-terminal residues being critical. Preferentially selects peptides having a highly hydrophobic residue at position 3 and hydrophobic or charged residues at the C-terminal anchor. Proline at position 2 has the most destabilizing effect (PubMed:11274390, PubMed:7500034, PubMed:9256420). As a component of the peptide loading complex (PLC), acts as a molecular scaffold essential for peptide-MHCI assembly and antigen presentation (PubMed:1538751, PubMed:25377891, PubMed:26611325)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q03519/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TAP2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TAP2","total_profiled":1310},"omim":[{"mim_id":"620813","title":"MHC CLASS I DEFICIENCY 2; MHC1D2","url":"https://www.omim.org/entry/620813"},{"mim_id":"612825","title":"SEC14-LIKE LIPID-BINDING PROTEIN 4; SEC14L4","url":"https://www.omim.org/entry/612825"},{"mim_id":"612824","title":"SEC14-LIKE LIPID-BINDING PROTEIN 3; SEC14L3","url":"https://www.omim.org/entry/612824"},{"mim_id":"605464","title":"ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 8; ABCB8","url":"https://www.omim.org/entry/605464"},{"mim_id":"605453","title":"ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 9; ABCB9","url":"https://www.omim.org/entry/605453"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TAP2"},"hgnc":{"alias_symbol":["PSF2","RING11","D6S217E"],"prev_symbol":["ABCB3"]},"alphafold":{"accession":"Q03519","domains":[{"cath_id":"1.20.1560.10","chopping":"127-289_432-449","consensus_level":"medium","plddt":85.5256,"start":127,"end":449},{"cath_id":"3.40.50.300","chopping":"467-680","consensus_level":"high","plddt":87.7366,"start":467,"end":680},{"cath_id":"1.20.120","chopping":"5-118","consensus_level":"high","plddt":64.968,"start":5,"end":118},{"cath_id":"1.10.287","chopping":"290-403","consensus_level":"medium","plddt":90.8358,"start":290,"end":403}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03519","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q03519-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q03519-F1-predicted_aligned_error_v6.png","plddt_mean":82.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TAP2","jax_strain_url":"https://www.jax.org/strain/search?query=TAP2"},"sequence":{"accession":"Q03519","fasta_url":"https://rest.uniprot.org/uniprotkb/Q03519.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q03519/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03519"}},"corpus_meta":[{"pmid":"8428770","id":"PMC_8428770","title":"Alleles and haplotypes of the MHC-encoded ABC transporters TAP1 and TAP2.","date":"1993","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/8428770","citation_count":227,"is_preprint":false},{"pmid":"10749979","id":"PMC_10749979","title":"High resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot.","date":"2000","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10749979","citation_count":169,"is_preprint":false},{"pmid":"7809108","id":"PMC_7809108","title":"Characteristics of peptide and major histocompatibility complex class I/beta 2-microglobulin binding to the transporters associated with antigen processing (TAP1 and TAP2).","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7809108","citation_count":152,"is_preprint":false},{"pmid":"9485029","id":"PMC_9485029","title":"HLA class I antigen and transporter associated with antigen processing (TAP1 and TAP2) down-regulation in high-grade primary breast carcinoma lesions.","date":"1998","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9485029","citation_count":145,"is_preprint":false},{"pmid":"12694570","id":"PMC_12694570","title":"Total loss of MHC class I in colorectal tumors can be explained by two molecular pathways: beta2-microglobulin inactivation in MSI-positive tumors and LMP7/TAP2 downregulation in MSI-negative tumors.","date":"2003","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/12694570","citation_count":127,"is_preprint":false},{"pmid":"8477801","id":"PMC_8477801","title":"Linkage disequilibrium between TAP2 variants and HLA class II alleles; no primary association between TAP2 variants and insulin-dependent diabetes mellitus.","date":"1993","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8477801","citation_count":102,"is_preprint":false},{"pmid":"8344720","id":"PMC_8344720","title":"TAP1 and TAP2 polymorphism in coeliac disease.","date":"1993","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/8344720","citation_count":77,"is_preprint":false},{"pmid":"15774487","id":"PMC_15774487","title":"LMP7/TAP2 gene polymorphisms and HPV infection in esophageal carcinoma patients from a high incidence area in China.","date":"2005","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/15774487","citation_count":73,"is_preprint":false},{"pmid":"8765016","id":"PMC_8765016","title":"A point mutation in the human transporter associated with antigen processing (TAP2) alters the peptide transport specificity.","date":"1996","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8765016","citation_count":70,"is_preprint":false},{"pmid":"9324024","id":"PMC_9324024","title":"Association of a new allele of the TAP2 gene, TAP2*Bky2 (Val577), with susceptibility to Sjögren's syndrome.","date":"1997","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/9324024","citation_count":65,"is_preprint":false},{"pmid":"11099504","id":"PMC_11099504","title":"Walker A lysine mutations of TAP1 and TAP2 interfere with peptide translocation but not peptide binding.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11099504","citation_count":64,"is_preprint":false},{"pmid":"11119603","id":"PMC_11119603","title":"Interferon regulatory factor 7 mediates activation of Tap-2 by Epstein-Barr virus latent membrane protein 1.","date":"2001","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/11119603","citation_count":58,"is_preprint":false},{"pmid":"12648582","id":"PMC_12648582","title":"TAP1, TAP2, and HLA-DR2 alleles are predictors of cervical cancer risk.","date":"2003","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12648582","citation_count":54,"is_preprint":false},{"pmid":"11861289","id":"PMC_11861289","title":"Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11861289","citation_count":54,"is_preprint":false},{"pmid":"16210614","id":"PMC_16210614","title":"Critical role for the tapasin-docking site of TAP2 in the functional integrity of the MHC class I-peptide-loading complex.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16210614","citation_count":54,"is_preprint":false},{"pmid":"10471632","id":"PMC_10471632","title":"Analysis of MHC encoded antigen-processing genes TAP1 and TAP2 polymorphisms in sarcoidosis.","date":"1999","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10471632","citation_count":53,"is_preprint":false},{"pmid":"14604968","id":"PMC_14604968","title":"The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/14604968","citation_count":52,"is_preprint":false},{"pmid":"16174096","id":"PMC_16174096","title":"Identification of domain boundaries within the N-termini of TAP1 and TAP2 and their importance in tapasin binding and tapasin-mediated increase in peptide loading of MHC class I.","date":"2005","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16174096","citation_count":51,"is_preprint":false},{"pmid":"8393798","id":"PMC_8393798","title":"TAP2-defective RMA-S cells present Sendai virus antigen to cytotoxic T lymphocytes.","date":"1993","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8393798","citation_count":48,"is_preprint":false},{"pmid":"1460275","id":"PMC_1460275","title":"T cell recognition of QA-1b antigens on cells lacking a functional Tap-2 transporter.","date":"1992","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1460275","citation_count":48,"is_preprint":false},{"pmid":"7678769","id":"PMC_7678769","title":"Induction of a tomato anionic peroxidase gene (tap1) by wounding in transgenic tobacco and activation of tap1/GUS and tap2/GUS chimeric gene fusions in transgenic tobacco by wounding and pathogen attack.","date":"1993","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7678769","citation_count":47,"is_preprint":false},{"pmid":"16634865","id":"PMC_16634865","title":"Analysis of IL1B, TAP1, TAP2 and IKBL polymorphisms on susceptibility to tuberculosis.","date":"2006","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/16634865","citation_count":46,"is_preprint":false},{"pmid":"8523185","id":"PMC_8523185","title":"Association of HLA class I antigen deficiency related to a TAP2 gene mutation with familial bronchiectasis.","date":"1995","source":"The Journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/8523185","citation_count":46,"is_preprint":false},{"pmid":"12213826","id":"PMC_12213826","title":"Tapasin interacts with the membrane-spanning domains of both TAP subunits and enhances the structural stability of TAP1 x TAP2 Complexes.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12213826","citation_count":43,"is_preprint":false},{"pmid":"19609238","id":"PMC_19609238","title":"Maturation pathways of dendritic cells determine TAP1 and TAP2 levels and cross-presenting function.","date":"2009","source":"Journal of immunotherapy (Hagerstown, Md. : 1997)","url":"https://pubmed.ncbi.nlm.nih.gov/19609238","citation_count":42,"is_preprint":false},{"pmid":"8847232","id":"PMC_8847232","title":"Family study of linkage disequilibrium between TAP2 transporter and HLA class II genes. Absence of TAP2 contribution to association with insulin-dependent diabetes mellitus.","date":"1995","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8847232","citation_count":42,"is_preprint":false},{"pmid":"8206525","id":"PMC_8206525","title":"The distribution of Tap2 alleles among laboratory rat RT1 haplotypes.","date":"1994","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/8206525","citation_count":42,"is_preprint":false},{"pmid":"9027960","id":"PMC_9027960","title":"Polymorphisms of TAP1 and TAP2 genes in Graves' disease.","date":"1997","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9027960","citation_count":41,"is_preprint":false},{"pmid":"7759306","id":"PMC_7759306","title":"TAP2 gene polymorphism contributes to genetic susceptibility to multiple sclerosis.","date":"1995","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7759306","citation_count":41,"is_preprint":false},{"pmid":"29091951","id":"PMC_29091951","title":"Downregulation of TAP1 and TAP2 in early stage breast cancer.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29091951","citation_count":40,"is_preprint":false},{"pmid":"27447835","id":"PMC_27447835","title":"Expression Quantitative Trait Locus Mapping Studies in Mid-secretory Phase Endometrial Cells Identifies HLA-F and TAP2 as Fecundability-Associated Genes.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27447835","citation_count":40,"is_preprint":false},{"pmid":"15205935","id":"PMC_15205935","title":"The dominant MHC class I gene is adjacent to the polymorphic TAP2 gene in the duck, Anas platyrhynchos.","date":"2004","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/15205935","citation_count":40,"is_preprint":false},{"pmid":"29879547","id":"PMC_29879547","title":"The influence of TAP1 and TAP2 gene polymorphisms on TAP function and its inhibition by viral immune evasion proteins.","date":"2018","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29879547","citation_count":38,"is_preprint":false},{"pmid":"12047747","id":"PMC_12047747","title":"Interactions formed by individually expressed TAP1 and TAP2 polypeptide subunits.","date":"2002","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12047747","citation_count":38,"is_preprint":false},{"pmid":"9041658","id":"PMC_9041658","title":"Polymorphisms of the TAP2 gene may influence antibody response to live measles vaccine virus.","date":"1997","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/9041658","citation_count":37,"is_preprint":false},{"pmid":"10220507","id":"PMC_10220507","title":"Involvement of transporter associated with antigen processing 2 (TAP2) gene polymorphisms in hepatitis C virus infection.","date":"1999","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/10220507","citation_count":36,"is_preprint":false},{"pmid":"8162639","id":"PMC_8162639","title":"Polymorphisms in the TAP2 gene and their association with rheumatoid arthritis.","date":"1994","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/8162639","citation_count":35,"is_preprint":false},{"pmid":"7558930","id":"PMC_7558930","title":"TAP2 association with insulin-dependent diabetes mellitus is secondary to HLA-DQB1.","date":"1995","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7558930","citation_count":35,"is_preprint":false},{"pmid":"17244610","id":"PMC_17244610","title":"Multiple residues in the transmembrane helix and connecting peptide of mouse tapasin stabilize the transporter associated with the antigen-processing TAP2 subunit.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17244610","citation_count":34,"is_preprint":false},{"pmid":"8189046","id":"PMC_8189046","title":"Expression of secreted and glycosylphosphatidylinositol-bound Qa-2 molecules is dependent on functional TAP-2 peptide transporter.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8189046","citation_count":34,"is_preprint":false},{"pmid":"9709177","id":"PMC_9709177","title":"Differential contribution of HLA-DR, DQ, and TAP2 alleles to systemic lupus erythematosus susceptibility in Spanish patients: role of TAP2*01 alleles in Ro autoantibody production.","date":"1998","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/9709177","citation_count":33,"is_preprint":false},{"pmid":"15259011","id":"PMC_15259011","title":"Biological function of the soluble CEACAM1 protein and implications in TAP2-deficient patients.","date":"2004","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15259011","citation_count":32,"is_preprint":false},{"pmid":"16624807","id":"PMC_16624807","title":"Biogenesis of functional antigenic peptide transporter TAP requires assembly of pre-existing TAP1 with newly synthesized TAP2.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16624807","citation_count":32,"is_preprint":false},{"pmid":"9368636","id":"PMC_9368636","title":"Major histocompatibility complex class I molecules interact with both subunits of the transporter associated with antigen processing, TAP1 and TAP2.","date":"1997","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9368636","citation_count":32,"is_preprint":false},{"pmid":"15219464","id":"PMC_15219464","title":"Role of TAP-1 and/or TAP-2 antigen presentation defects in tumorigenicity of mouse melanoma.","date":"2004","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15219464","citation_count":31,"is_preprint":false},{"pmid":"24175803","id":"PMC_24175803","title":"Association of TAP1 and TAP2 gene polymorphisms with hematological malignancies.","date":"2013","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24175803","citation_count":27,"is_preprint":false},{"pmid":"17068338","id":"PMC_17068338","title":"Catalytic site modifications of TAP1 and TAP2 and their functional consequences.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17068338","citation_count":27,"is_preprint":false},{"pmid":"8813124","id":"PMC_8813124","title":"Cell cycle-dependent expression of TAP1, TAP2, and HLA-B27 messenger RNAs in a human breast cancer cell line.","date":"1996","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/8813124","citation_count":27,"is_preprint":false},{"pmid":"16595160","id":"PMC_16595160","title":"A TAP2 genotype associated with Alzheimer's disease in APOE4 carriers.","date":"2006","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/16595160","citation_count":27,"is_preprint":false},{"pmid":"6829609","id":"PMC_6829609","title":"Brief clinical report: ring-11 chromosome: phenotype-karyotype correlation with deletions of 11q.","date":"1983","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/6829609","citation_count":27,"is_preprint":false},{"pmid":"12634240","id":"PMC_12634240","title":"TAP1 and TAP2 polymorphisms analysis in northwestern Colombian patients with systemic lupus erythematosus.","date":"2003","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/12634240","citation_count":25,"is_preprint":false},{"pmid":"11011155","id":"PMC_11011155","title":"A half-type ABC transporter TAPL is highly conserved between rodent and man, and the human gene is not responsive to interferon-gamma in contrast to TAP1 and TAP2.","date":"2000","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11011155","citation_count":25,"is_preprint":false},{"pmid":"8208914","id":"PMC_8208914","title":"Analysis of HLA-class-II-encoded antigen-processing genes TAP1 and TAP2 in primary biliary cirrhosis.","date":"1994","source":"The Quarterly journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8208914","citation_count":25,"is_preprint":false},{"pmid":"25448698","id":"PMC_25448698","title":"The ABC transporter, AbcB3, mediates cAMP export in D. discoideum development.","date":"2014","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/25448698","citation_count":24,"is_preprint":false},{"pmid":"12047361","id":"PMC_12047361","title":"TAP1 and TAP2 gene polymorphism in rheumatoid arthritis in a population in eastern France.","date":"2002","source":"European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/12047361","citation_count":24,"is_preprint":false},{"pmid":"7578413","id":"PMC_7578413","title":"Tap-1 and Tap-2 gene therapy selectively restores conformationally dependent HLA Class I expression in type I diabetic cells.","date":"1995","source":"Human gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/7578413","citation_count":24,"is_preprint":false},{"pmid":"7558936","id":"PMC_7558936","title":"Reevaluation of the relative risk for susceptibility to celiac disease of HLA-DRB1, -DQA1, -DQB1, -DPB1, and -TAP2 alleles in a French population.","date":"1995","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7558936","citation_count":24,"is_preprint":false},{"pmid":"17192492","id":"PMC_17192492","title":"Genetic control of alternative splicing in the TAP2 gene: possible implication in the genetics of type 1 diabetes.","date":"2007","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/17192492","citation_count":24,"is_preprint":false},{"pmid":"12234057","id":"PMC_12234057","title":"Differential regulation of the expression of transporters associated with antigen processing, TAP1 and TAP2, by cytokines and lipopolysaccharide in primary human macrophages.","date":"2002","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/12234057","citation_count":23,"is_preprint":false},{"pmid":"9914331","id":"PMC_9914331","title":"Identification and genetic mapping of Xenopus TAP2 genes.","date":"1999","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/9914331","citation_count":23,"is_preprint":false},{"pmid":"8181966","id":"PMC_8181966","title":"Associations between alleles of the major histocompatibility complex-encoded ABC transporter gene TAP2, HLA class II alleles, and celiac disease susceptibility.","date":"1994","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8181966","citation_count":23,"is_preprint":false},{"pmid":"8147927","id":"PMC_8147927","title":"Association of TAP2 polymorphism with rheumatoid arthritis is secondary to allelic association with HLA-DRB1.","date":"1994","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/8147927","citation_count":23,"is_preprint":false},{"pmid":"9062964","id":"PMC_9062964","title":"Analysis of allelic variation of the TAP2 gene in sarcoidosis.","date":"1997","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9062964","citation_count":23,"is_preprint":false},{"pmid":"11529920","id":"PMC_11529920","title":"Molecular studies and NK cell function of a new case of TAP2 homozygous human deficiency.","date":"2001","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11529920","citation_count":22,"is_preprint":false},{"pmid":"7928442","id":"PMC_7928442","title":"TAP1 and TAP2 polymorphism in multiple sclerosis patients.","date":"1994","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7928442","citation_count":22,"is_preprint":false},{"pmid":"8311559","id":"PMC_8311559","title":"Polymorphisms of the TAP2 transporter gene in systemic lupus erythematosus.","date":"1994","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/8311559","citation_count":21,"is_preprint":false},{"pmid":"26996113","id":"PMC_26996113","title":"Association of TAP1 and TAP2 Gene Polymorphisms with Susceptibility to Pulmonary Tuberculosis.","date":"2016","source":"Iranian journal of allergy, asthma, and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26996113","citation_count":20,"is_preprint":false},{"pmid":"8061113","id":"PMC_8061113","title":"Enhanced expression of HLA-A,B,C and inducibility of TAP-1, TAP-2, and HLA-A,B,C by interferon-gamma in a multidrug-resistant small cell lung cancer line.","date":"1994","source":"Lymphokine and cytokine research","url":"https://pubmed.ncbi.nlm.nih.gov/8061113","citation_count":20,"is_preprint":false},{"pmid":"11468516","id":"PMC_11468516","title":"Reduced expression of TAP-1 and TAP-2 in posterior uveal melanoma is associated with progression to metastatic disease.","date":"2001","source":"Melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/11468516","citation_count":20,"is_preprint":false},{"pmid":"7737270","id":"PMC_7737270","title":"Surface expression of beta 2-microglobulin-associated thymus-leukemia antigen is independent of TAP2.","date":"1995","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7737270","citation_count":20,"is_preprint":false},{"pmid":"16037391","id":"PMC_16037391","title":"Functional aberrant expression of CCR2 receptor on chronically activated NK cells in patients with TAP-2 deficiency.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16037391","citation_count":18,"is_preprint":false},{"pmid":"12505156","id":"PMC_12505156","title":"Functional cysteine-less subunits of the transporter associated with antigen processing (TAP1 and TAP2) by de novo gene assembly.","date":"2003","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12505156","citation_count":18,"is_preprint":false},{"pmid":"7645042","id":"PMC_7645042","title":"Effects of MHC-encoded TAP1 and TAP2 gene polymorphism and matching on kidney graft rejection.","date":"1995","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/7645042","citation_count":17,"is_preprint":false},{"pmid":"18071882","id":"PMC_18071882","title":"Significance of transporter associated with antigen processing 2 (TAP2) gene polymorphisms in susceptibility to dengue viral infection.","date":"2008","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18071882","citation_count":17,"is_preprint":false},{"pmid":"8002377","id":"PMC_8002377","title":"Analysis of TAP2 and HLA-DP gene polymorphism in psoriasis.","date":"1994","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8002377","citation_count":16,"is_preprint":false},{"pmid":"14749980","id":"PMC_14749980","title":"Association of TAP2 gene polymorphisms in Chinese patients with rheumatoid arthritis.","date":"2003","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/14749980","citation_count":16,"is_preprint":false},{"pmid":"9226129","id":"PMC_9226129","title":"Polymorphisms of TAP1 and TAP2 genes in German patients with type 1 diabetes mellitus.","date":"1997","source":"European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/9226129","citation_count":16,"is_preprint":false},{"pmid":"34589184","id":"PMC_34589184","title":"Structural determinants of peptide-dependent TAP1-TAP2 transit passage targeted by viral proteins and altered by cancer-associated mutations.","date":"2021","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/34589184","citation_count":15,"is_preprint":false},{"pmid":"11294565","id":"PMC_11294565","title":"Genotyping TAP2 variants in North American Caucasians, Brazilians, and Africans.","date":"2001","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/11294565","citation_count":15,"is_preprint":false},{"pmid":"7589884","id":"PMC_7589884","title":"HLA DQA1-DQB1-TAP2 haplotypes in IDDM families: no evidence for an additional contribution to disease risk by the TAP2 locus.","date":"1995","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/7589884","citation_count":15,"is_preprint":false},{"pmid":"25749172","id":"PMC_25749172","title":"Reduced Expression of the Antigen Processing Machinery Components TAP2, LMP2, and LMP7 in Tonsillar and Base of Tongue Cancer and Implications for Clinical Outcome.","date":"2015","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25749172","citation_count":14,"is_preprint":false},{"pmid":"17245734","id":"PMC_17245734","title":"The role of TAP1 and TAP2 gene polymorphism in idiopathic bronchiectasis in children.","date":"2007","source":"Pediatric pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/17245734","citation_count":13,"is_preprint":false},{"pmid":"9303338","id":"PMC_9303338","title":"TAP1 and TAP2 genes in nickel allergy.","date":"1997","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9303338","citation_count":13,"is_preprint":false},{"pmid":"25846714","id":"PMC_25846714","title":"Association of TAP1 and TAP2 genes with susceptibility to pulmonary tuberculosis in Koreans.","date":"2015","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/25846714","citation_count":13,"is_preprint":false},{"pmid":"9266943","id":"PMC_9266943","title":"Assessment of intracellular TAP-1 and TAP-2 in conjunction with surface MHC class I in plasma cells from patients with multiple myeloma.","date":"1997","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/9266943","citation_count":13,"is_preprint":false},{"pmid":"33060735","id":"PMC_33060735","title":"TAP2, a peptide antagonist of Toll-like receptor 4, attenuates pain and cartilage degradation in a monoiodoacetate-induced arthritis rat model.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33060735","citation_count":12,"is_preprint":false},{"pmid":"24586191","id":"PMC_24586191","title":"Natural polymorphisms in Tap2 influence negative selection and CD4∶CD8 lineage commitment in the rat.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24586191","citation_count":12,"is_preprint":false},{"pmid":"27745831","id":"PMC_27745831","title":"An Ancient Fecundability-Associated Polymorphism Switches a Repressor into an Enhancer of Endometrial TAP2 Expression.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27745831","citation_count":12,"is_preprint":false},{"pmid":"8851724","id":"PMC_8851724","title":"The human leukocyte antigen TAP2 gene defines the centromeric limit of melanoma susceptibility on chromosome 6p.","date":"1996","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/8851724","citation_count":12,"is_preprint":false},{"pmid":"9672156","id":"PMC_9672156","title":"New TAP2 polymorphisms in Africans.","date":"1998","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9672156","citation_count":12,"is_preprint":false},{"pmid":"1672656","id":"PMC_1672656","title":"Molecular analysis of tap2, an anther-specific gene from Antirrhinum majus.","date":"1991","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/1672656","citation_count":12,"is_preprint":false},{"pmid":"8913653","id":"PMC_8913653","title":"Association of TAP1 and TAP2 with systemic sclerosis in Japanese.","date":"1996","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/8913653","citation_count":11,"is_preprint":false},{"pmid":"9510369","id":"PMC_9510369","title":"Development and characterization of mouse anti-human LMP2, LMP7, TAP1 and TAP2 monoclonal antibodies.","date":"1998","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/9510369","citation_count":11,"is_preprint":false},{"pmid":"7797612","id":"PMC_7797612","title":"TAP2 polymorphisms in Australian multiple sclerosis patients.","date":"1995","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/7797612","citation_count":11,"is_preprint":false},{"pmid":"1300236","id":"PMC_1300236","title":"TAP1 and TAP2 transporter genes and predisposition to insulin dependent diabetes mellitus.","date":"1992","source":"Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie","url":"https://pubmed.ncbi.nlm.nih.gov/1300236","citation_count":11,"is_preprint":false},{"pmid":"9014588","id":"PMC_9014588","title":"Polymorphisms of the TAP1 and TAP2 transporter genes in Japanese SLE.","date":"1996","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/9014588","citation_count":10,"is_preprint":false},{"pmid":"20193774","id":"PMC_20193774","title":"TAP1 and TAP2 gene polymorphisms in childhood cystic echinococcosis.","date":"2010","source":"Parasitology international","url":"https://pubmed.ncbi.nlm.nih.gov/20193774","citation_count":10,"is_preprint":false},{"pmid":"17982230","id":"PMC_17982230","title":"TAP1 and TAP2 gene polymorphisms in Korean patients with allergic rhinitis.","date":"2007","source":"Journal of Korean medical science","url":"https://pubmed.ncbi.nlm.nih.gov/17982230","citation_count":10,"is_preprint":false},{"pmid":"19721454","id":"PMC_19721454","title":"Mouse strains with point mutations in TAP1 and TAP2.","date":"2009","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19721454","citation_count":10,"is_preprint":false},{"pmid":"36227411","id":"PMC_36227411","title":"Delayed Diagnosis of Chronic Necrotizing Granulomatous Skin Lesions due to TAP2 Deficiency.","date":"2022","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36227411","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50239,"output_tokens":5713,"usd":0.118206,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14219,"output_tokens":5145,"usd":0.09986,"stage2_stop_reason":"end_turn"},"total_usd":0.218066,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Both TAP1 and TAP2 subunits are photolabeled by peptide photoprobes, indicating that elements of both subunits compose the peptide-recognition site. Efficient formation of the peptide-binding site requires coexpression of TAP1 and TAP2, supporting the notion that TAP functions as a heterodimer. MHC class I/beta2m dimers associate with TAP1 but are not detectable with TAP2 alone, suggesting that the TAP1 chain is the primary site of MHC class I/beta2m interaction.\",\n      \"method\": \"TAP photoaffinity labeling with photopeptide analogues; transfectant cell lines expressing TAP1 and TAP2 individually and together; peptide translocation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro assays (photoaffinity labeling, translocation assays, co-expression studies) in a single rigorous study\",\n      \"pmids\": [\"7809108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Peptide transport specificity with regard to the C-terminal amino acid of transported peptides is mainly determined by TAP2. The N-terminal region (residues 1–361) of TAP2 critically controls selective transport of peptides with C-terminal positively charged residues. A single point mutation in human TAP2 (374A→D) drastically alters the transport pattern, demonstrating that single residues in TAP2 control peptide selectivity.\",\n      \"method\": \"Interspecies TAP hybrid construction; point mutagenesis of hTAP2; expression in Sf9 insect cells and TAP-deficient T2 cells; peptide transport assays with 20 C-terminal variants\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in insect cells plus mutagenesis with functional transport assay, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"8765016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Walker A lysine mutation in TAP2 (K509M) does not significantly impair nucleotide binding relative to wild-type TAP2, unlike the equivalent TAP1 mutation. TAP1·TAP2(K509M) complexes show undetectable peptide translocation, while TAP1(K544M)·TAP2 complexes retain low-level translocation, indicating that both NBDs must be functional for efficient peptide translocation and suggesting distinct roles for TAP1 and TAP2 NBDs in a single translocation cycle.\",\n      \"method\": \"Site-directed mutagenesis of Walker A motifs; expression in insect cells; nucleotide binding assays; fluorescence quenching peptide binding assays; peptide translocation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in insect cells with mutagenesis plus multiple functional readouts (nucleotide binding, peptide binding, translocation) in one rigorous study\",\n      \"pmids\": [\"11099504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Tapasin binds to both TAP1 and TAP2 via their membrane-spanning regions; interactions with the nucleotide binding domain alone are not observed. Tapasin is not required for high-affinity peptide binding to TAP1·TAP2 complexes and slightly reduces peptide-binding affinity. However, tapasin and nucleotides together stabilize the peptide-binding site against inactivation at near-physiological temperatures, enhancing structural stability of both TAP subunits.\",\n      \"method\": \"Tapasin co-expression with TAP variants in insect cells; truncation and chimera constructs; thermal stability assays; peptide binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with defined constructs plus multiple functional readouts (binding, thermal stability) in one study\",\n      \"pmids\": [\"12213826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TAP2 catalytic site residues Glu632 (Walker B) and His661 (switch region) are critical for peptide translocation and MHC class I surface expression. Alterations at these residues significantly reduced TAP activity, whereas equivalent mutations in the degenerate TAP1 catalytic site (Asp668, Gln701) had only small effects. The TAP2 nucleotide-binding site (second site) is therefore the main catalytically active site driving peptide transport, consistent with an asymmetric one-main-active-site mechanism.\",\n      \"method\": \"Site-directed mutagenesis of catalytic residues in TAP1 and TAP2; expression in TAP-deficient cells; peptide translocation assays; MHC class I surface expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of both catalytic sites combined with two orthogonal functional readouts in one rigorous study\",\n      \"pmids\": [\"17068338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Truncation of the N-terminal domain of TAP2 (but not TAP1) produces peptide-loading complexes that fail to generate stable MHC class I–peptide complexes, correlating with substantially reduced recruitment of accessory chaperones into the PLC. This identifies the tapasin-docking site on TAP2 as critical for the functional integrity of the MHC class I peptide-loading complex.\",\n      \"method\": \"Expression of N-terminally truncated TAP variants; co-immunoprecipitation of PLC components; MHC class I surface expression assays; functional peptide-loading assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean domain-deletion approach with multiple orthogonal readouts (co-IP, surface expression, peptide loading) in one study\",\n      \"pmids\": [\"16210614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"N-terminal domains of both TAP1 and TAP2 (defined by proteolytic cleavage sites at residues 131 of TAP1 and 88 of TAP2) are dispensable for peptide and nucleotide binding and support peptide translocation (albeit with reduced efficiency), but are required for tapasin binding and for the tapasin-mediated enhancement of MHC class I peptide loading.\",\n      \"method\": \"Expression and purification of human TAP1/TAP2 complexes from insect cells; limited proteolysis; N-terminal truncation variants; peptide binding and translocation assays; insect cell-based reconstitution of MHC class I loading pathway; tapasin binding assays\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in insect cells with defined truncations, multiple orthogonal assays (binding, translocation, MHC loading) in one study\",\n      \"pmids\": [\"16174096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TAP2 is highly unstable when expressed in isolation and requires heterodimerization with TAP1 for stable expression. Functional TAP biogenesis requires assembly of pre-existing TAP1 with newly synthesized TAP2 (but not vice versa). The core transmembrane domain of TAP2 is necessary and sufficient for functional complex formation with pre-existing TAP1.\",\n      \"method\": \"In vitro expression system; pulse-chase/stability assays; domain truncation and chimera constructs; functional peptide transport assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined domain constructs and multiple functional readouts including translocation assays\",\n      \"pmids\": [\"16624807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Multiple residues in the transmembrane domain (TMD) and ER-luminal connecting peptide (CP) of tapasin are required to stabilize the TAP2 subunit. A conserved Lys in the center of the tapasin TMD plus four predicted helix-face neighbors must be mutated together to abolish TAP2 stabilization. A highly conserved Glu in the ER-luminal CP also strongly contributes to TAP2 stabilization. Loss of TAP2 stabilization impairs MHC class I surface expression.\",\n      \"method\": \"Mutational analysis of tapasin TMD and CP; transfection of tapasin-deficient cells; Western blot quantification of TAP2 protein levels; MHC class I surface expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — detailed systematic mutagenesis with clean tapasin-deficient cell background and multiple orthogonal readouts\",\n      \"pmids\": [\"17244610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Individual TAP2 polypeptide subunits, when expressed alone, interact with multiple MHC class I alleles (HLA-A2, -B51, -A*2501, -B*2704, -B*3501, -B*4402) and can form peptide-loading complexes. TAP2, but not TAP1, has the ability to form homodimers both in whole cells and in detergent lysates, as demonstrated by chemical cross-linking.\",\n      \"method\": \"Immunoprecipitation of individually expressed TAP subunits in TAP-deficient T2 cells; recombinant vaccinia virus expression of HLA alleles; chemical cross-linking\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP/cross-linking approach, single lab, but multiple HLA alleles tested providing convergent evidence\",\n      \"pmids\": [\"12047747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MHC class I molecules interact with both TAP1 and TAP2 subunits. In TAP-deficient T2 cells expressing rat TAP2 alone, MHC class I molecules associate with TAP2, and this interaction also involves calreticulin and tapasin, indicating that the interaction of MHC class I with TAP is not exclusive to TAP1.\",\n      \"method\": \"Immunoprecipitation from TAP-deficient T2 cells transfected with individual rat TAP subunits\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP experiment in a clean TAP-deficient background, single lab\",\n      \"pmids\": [\"9368636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"EBV latent membrane protein 1 (LMP-1) induces TAP2 expression via IRF-7 as a secondary mediator: LMP-1 stimulates IRF-7 expression, facilitates IRF-7 phosphorylation and nuclear translocation, and activated IRF-7 binds the TAP2 promoter ISRE element to activate TAP2 transcription. Only IRF-7A splice variant (not other isoforms) activates TAP2. TAP2 induction by LMP-1 requires an intact ISRE in the TAP2 promoter.\",\n      \"method\": \"Endogenous TAP2 induction assays in Burkitt's lymphoma cell lines; ectopic IRF-7 expression; TAP2 promoter reporter assays; formaldehyde cross-linking ChIP; gel mobility shift assay; cell complementation experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay, ChIP, EMSA, cell complementation) in one study establishing mechanistic pathway\",\n      \"pmids\": [\"11119603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"In the murine TAP2-defective RMA-S cell line, antigen presentation of Sendai virus via MHC class I is possible but requires 2–3 h longer incubation and ~10× higher virus dose compared to wild-type cells. Transfection of murine TAP1/TAP2 genes into RMA-S cells fully restores Sendai virus antigen presentation, confirming that TAP2 is required for efficient endogenous antigen presentation.\",\n      \"method\": \"CTL killing assays with TAP2-defective RMA-S cells vs. parental RMA; TAP1/TAP2 gene transfection rescue; brefeldin A sensitivity assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic rescue (transfection) with functional CTL readout, single lab\",\n      \"pmids\": [\"8393798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Expression of class Ib Qa-2 molecules (both GPI-anchored and soluble forms) requires functional TAP2: in TAP2-defective RMA-S cells, Qa-2 molecules behave as empty heterodimers unstable at 37°C but stabilized at 26°C, similar to class Ia molecules. A minor population of heat-resistant Qa-2 in RMA-S suggests a secondary TAP-independent peptide loading pathway.\",\n      \"method\": \"Temperature-shift stability assays; peptide loading assays; immunoprecipitation from TAP2-defective RMA-S cells vs. wild-type\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean TAP2-null genetic background with functional stability and peptide-loading readouts, single lab\",\n      \"pmids\": [\"8189046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TL (thymus-leukemia antigen), a class Ib MHC molecule, is expressed efficiently at the cell surface in the absence of functional TAP2 in RMA-S cells, unlike most MHC class I molecules. Surface TL in TAP2-deficient cells is associated with beta2m but heavy chains are cleaved to a ~38 kDa fragment, suggesting altered conformation when loaded without TAP2-dependent peptides.\",\n      \"method\": \"Expression of TL constructs in RMA and RMA-S cells; immunoprecipitation; SDS-PAGE; surface expression assays; temperature-shift assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean TAP2-null genetic background with multiple biochemical readouts, single lab\",\n      \"pmids\": [\"7737270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cysteine-less TAP1 and TAP2 subunits (all 19 cysteines replaced by de novo gene synthesis) are functional with respect to ATP-dependent peptide transport and inhibition by viral TAP inhibitor ICP47, and restore MHC class I maturation and trafficking, demonstrating that none of the cysteine residues in TAP1 or TAP2 are individually essential for core transport function.\",\n      \"method\": \"De novo gene synthesis of cysteine-less TAP1/TAP2; expression in TAP-deficient human fibroblasts; peptide transport assays; ICP47 inhibition assay; MHC class I surface expression assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstitution with functional readout (transport, MHC expression), single lab, single paper\",\n      \"pmids\": [\"12505156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A point mutation in mouse TAP2 (Thr293Pro) causes severe reduction in TAP2 protein without affecting mRNA levels, and also decreases TAP1 protein levels, demonstrating a role for mouse TAP2 in stabilizing TAP1 protein expression. Mice with defective TAP2 show very low MHC class I surface expression and few CD8+ T cells.\",\n      \"method\": \"ENU mutagenesis screen; genotyping; mRNA and protein expression analysis (Western blot); flow cytometry for MHC class I and CD8+ T cells\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — point-mutant mouse model with defined molecular lesion and multiple cellular readouts, single lab\",\n      \"pmids\": [\"19721454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Natural polymorphisms in rat Tap2 influence the peptide repertoire loaded onto MHC class I molecules, which in turn affects negative selection and CD4:CD8 lineage commitment of thymocytes. A recombination between RT1-A (MHC class I) and Tap2 alleles revealed that the restricted peptide repertoire conferred by a Tap2 variant leads to reduced negative selection of CD8 single-positive thymocytes.\",\n      \"method\": \"QTL mapping in outbred Heterogeneous Stock rats; MHC-recombinant congenic strain panel; flow cytometry for thymocyte subsets and MHC expression; genetic epistasis analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by genetic recombinant congenic panel with defined cellular phenotype, replicated across multiple strains\",\n      \"pmids\": [\"24586191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TAP2 coding SNP alleles influence differential splicing into two isoforms with alternative C-terminals that have distinct peptide selectivities. The G (Ala) allele at codon 665 is more than twice as abundant in isoform NM_000544, while isoform NM_018833 is derived almost exclusively from chromosomes carrying the A (Thr) allele, providing a plausible functional mechanism by which coding TAP2 polymorphisms may indirectly alter peptide selectivity.\",\n      \"method\": \"Allele-specific relative isoform quantification in heterozygous lymphoblastoid cell lines; transmission disequilibrium test in type 1 diabetes families\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct allele-isoform quantification in primary cells with two orthogonal analyses, single lab\",\n      \"pmids\": [\"17192492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Transfection of the Tap-2 gene into RMA-S (TAP2-defective) cells restores surface expression of QA-1b class Ib molecules and rescues recognition by Qdm-dependent (but not all Qdm-independent) anti-Qa-1 CTL, demonstrating that TAP2 is required for loading of specific peptides onto Qa-1b and that Qdm encodes a peptide whose surface expression depends on the TAP transporter.\",\n      \"method\": \"Tap-2 gene transfection into RMA-S cells; CTL killing assays with Qdm-dependent and independent clones\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic rescue with functional CTL readout, single lab\",\n      \"pmids\": [\"1460275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Naturally occurring TAP1 and TAP2 polymorphisms have no or limited effect on peptide transport or MHC class I surface expression. Herpesvirus-encoded TAP inhibitors (US6, ICP47, BNLF2a) inhibit a broad spectrum of TAP1/TAP2 variant combinations, indicating that viral immune evasion targets TAP in a polymorphism-independent manner.\",\n      \"method\": \"Expression of TAP1/TAP2 variant combinations; peptide transport assays; MHC class I surface expression assays; inhibition by viral TAP inhibitors\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transport assays across multiple variant combinations, single lab, orthogonal readouts\",\n      \"pmids\": [\"29879547\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TAP2 is an essential subunit of the heterodimeric ABC transporter TAP1/TAP2 that translocates antigenic peptides from the cytosol into the ER for MHC class I loading; TAP2 contributes to the shared peptide-recognition site, is the primary determinant of C-terminal peptide specificity via its N-terminal transmembrane region, harbors the main catalytically active nucleotide-binding site (Glu632/His661) driving transport, requires tapasin binding via its N-terminal domain and transmembrane region for PLC integrity and MHC class I loading efficiency, is stabilized by heterodimerization with TAP1 (biogenesis requires pre-existing TAP1 to assemble with newly synthesized TAP2), and is transcriptionally regulated by the IRF-7/LMP-1 axis through an ISRE element in its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TAP2 is an essential subunit of the heterodimeric ABC transporter TAP1/TAP2, which translocates antigenic peptides from the cytosol into the ER for loading onto MHC class I molecules and is required for efficient endogenous antigen presentation [#0, #12]. TAP functions only as a heterodimer: both subunits contribute elements of the shared peptide-recognition site, and TAP2 is intrinsically unstable in isolation, requiring assembly of newly synthesized TAP2 with pre-existing TAP1 — a process directed by its core transmembrane domain — for stable expression [#0, #7]. TAP2 is the primary determinant of C-terminal peptide selectivity, with its N-terminal region (residues 1–361) controlling transport of peptides bearing C-terminal charged residues and single point substitutions (e.g. 374A→D) drastically reshaping the transport pattern [#1]. Within the asymmetric nucleotide-binding architecture, the TAP2 catalytic site (Glu632 Walker B, His661 switch region) constitutes the main catalytically active site driving transport, whereas the degenerate TAP1 site contributes little, consistent with a one-main-active-site mechanism; nonetheless efficient translocation requires both NBDs to be functional [#2, #4]. TAP2's N-terminal domain and transmembrane region provide the tapasin-docking site essential for recruiting accessory chaperones into the peptide-loading complex and for stable MHC class I–peptide assembly, and tapasin together with nucleotides stabilizes the peptide-binding site against thermal inactivation [#3, #5, #6]. TAP2 is transcriptionally induced by the EBV LMP-1/IRF-7 axis, with activated IRF-7A binding an ISRE element in the TAP2 promoter [#11]. Natural TAP2 polymorphisms and alternative splicing shape the loaded peptide repertoire, with downstream consequences for thymocyte selection [#17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that TAP2 is functionally required for surface loading of specific TAP-dependent peptides, linking the transporter to a defined antigen repertoire.\",\n      \"evidence\": \"Tap-2 gene transfection rescue of RMA-S cells with Qdm-dependent CTL killing readout\",\n      \"pmids\": [\"1460275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which peptide features depend on TAP2 versus TAP1\", \"No biochemical reconstitution of transport\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Quantified the requirement for TAP2 in endogenous antigen presentation, showing it is needed for efficient (not absolute) MHC class I-restricted presentation.\",\n      \"evidence\": \"CTL killing assays in TAP2-defective RMA-S cells with TAP1/TAP2 transfection rescue\",\n      \"pmids\": [\"8393798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Residual presentation indicates a TAP-independent pathway not characterized\", \"Single virus model\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Resolved that the peptide-recognition site is composed of elements from both subunits and that TAP must function as a heterodimer, clarifying subunit roles in substrate binding.\",\n      \"evidence\": \"Photoaffinity labeling, co-expression studies, and translocation assays in transfectant cell lines\",\n      \"pmids\": [\"7809108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve residue-level contacts of each subunit\", \"Relative contribution of each subunit to specificity not quantified\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Extended the TAP2 requirement to class Ib molecules, showing Qa-2 stability depends on TAP2-mediated peptide loading.\",\n      \"evidence\": \"Temperature-shift stability and peptide-loading assays in TAP2-defective RMA-S cells\",\n      \"pmids\": [\"8189046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nature of the minor TAP-independent loading pathway unresolved\", \"Single class Ib molecule type\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstrated heterogeneity in TAP2 dependence among class Ib molecules, with TL reaching the surface without functional TAP2.\",\n      \"evidence\": \"Immunoprecipitation and surface expression of TL in RMA versus RMA-S cells\",\n      \"pmids\": [\"7737270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of TAP2-independent TL surface delivery not defined\", \"Functional consequence of heavy-chain cleavage unclear\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Localized C-terminal peptide selectivity primarily to TAP2 and to single residues in its N-terminal region, defining the structural basis of substrate discrimination.\",\n      \"evidence\": \"Interspecies TAP hybrids and point mutagenesis of hTAP2 with peptide transport assays in insect and T2 cells\",\n      \"pmids\": [\"8765016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism by which residue 374 alters specificity not resolved\", \"Did not map full set of selectivity-determining residues\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed MHC class I can associate with TAP2 (with calreticulin and tapasin), establishing that the loading complex contact is not exclusive to TAP1.\",\n      \"evidence\": \"Immunoprecipitation from T2 cells transfected with individual rat TAP subunits\",\n      \"pmids\": [\"9368636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP approach without reciprocal validation\", \"Physiological relevance of TAP2-alone association unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Distinguished the functional roles of the two NBDs, showing both must be functional for efficient translocation but with asymmetric behavior between TAP1 and TAP2 Walker A sites.\",\n      \"evidence\": \"Walker A mutagenesis with nucleotide-binding, peptide-binding, and translocation assays in insect cells\",\n      \"pmids\": [\"11099504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise ordering of NBD events in a cycle not defined\", \"Did not assign catalytic versus regulatory roles definitively\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped the tapasin interaction to the membrane-spanning regions of both subunits and defined tapasin's role in thermal stabilization rather than peptide affinity.\",\n      \"evidence\": \"Tapasin co-expression with TAP truncation/chimera constructs, thermal stability and peptide binding assays in insect cells\",\n      \"pmids\": [\"12213826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residue-level tapasin contacts on TAP2 not yet defined\", \"Did not address PLC chaperone recruitment\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Revealed that TAP2, unlike TAP1, can homodimerize and individually engage multiple MHC class I alleles, indicating subunit-specific assembly properties.\",\n      \"evidence\": \"Immunoprecipitation and chemical cross-linking of individually expressed subunits in T2 cells\",\n      \"pmids\": [\"12047747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional relevance of TAP2 homodimers in vivo unknown\", \"Single lab, single approach\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified the TAP2 N-terminal domain as critical for PLC integrity and chaperone recruitment, separating this role from core transport.\",\n      \"evidence\": \"N-terminal truncation variants with co-IP of PLC components and MHC class I surface/peptide-loading assays\",\n      \"pmids\": [\"16210614\", \"16174096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of all recruited accessory chaperones not fully enumerated\", \"Structural basis of N-terminal docking not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the TAP2 catalytic site (Glu632, His661) as the main catalytically active site driving transport, establishing an asymmetric one-main-active-site mechanism.\",\n      \"evidence\": \"Systematic catalytic-residue mutagenesis of both subunits with translocation and MHC class I surface assays\",\n      \"pmids\": [\"17068338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural transition states not resolved\", \"Role of degenerate TAP1 site beyond minor contribution unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that TAP2 biogenesis requires heterodimerization with pre-existing TAP1, with the core transmembrane domain sufficient for assembly.\",\n      \"evidence\": \"Stability/pulse-chase and domain-truncation constructs with functional transport assays\",\n      \"pmids\": [\"16624807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chaperones governing the ordered assembly not identified\", \"Folding intermediates not characterized\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined transcriptional control of TAP2 via the EBV LMP-1/IRF-7 axis acting on a promoter ISRE element.\",\n      \"evidence\": \"TAP2 promoter reporter assays, ChIP, EMSA, and IRF-7 complementation in lymphoma cell lines\",\n      \"pmids\": [\"11119603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other physiological transcriptional regulators of TAP2 not addressed\", \"In vivo relevance during EBV infection not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed tapasin TMD and ER-luminal residues stabilize TAP2 protein, linking tapasin docking to subunit stability and MHC class I expression.\",\n      \"evidence\": \"Systematic tapasin TMD/CP mutagenesis in tapasin-deficient cells with TAP2 Western blot and MHC class I surface assays\",\n      \"pmids\": [\"17244610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of stabilization (folding versus degradation protection) not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked TAP2 coding SNPs to differential isoform splicing with distinct peptide selectivities, providing a mechanism for polymorphism-driven repertoire variation.\",\n      \"evidence\": \"Allele-specific isoform quantification in heterozygous lymphoblastoid cells and TDT in type 1 diabetes families\",\n      \"pmids\": [\"17192492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct functional consequence on peptide loading not measured\", \"Disease association correlative\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated in vivo that TAP2 stabilizes TAP1 protein and is required for normal MHC class I expression and CD8+ T cell numbers.\",\n      \"evidence\": \"ENU mutant mouse (Thr293Pro) with mRNA/protein analysis and flow cytometry\",\n      \"pmids\": [\"19721454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of reciprocal TAP1 stabilization not defined\", \"Single point lesion\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed all cysteine residues are dispensable for core TAP transport function and viral inhibitor sensitivity.\",\n      \"evidence\": \"Cysteine-less TAP1/TAP2 de novo synthesis with transport, ICP47 inhibition, and MHC class I assays\",\n      \"pmids\": [\"12505156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single study\", \"Subtle effects on stability or kinetics not excluded\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected TAP2 polymorphism to the loaded peptide repertoire and downstream thymocyte negative selection and lineage commitment.\",\n      \"evidence\": \"QTL mapping and MHC-recombinant congenic rat panel with thymocyte flow cytometry and epistasis analysis\",\n      \"pmids\": [\"24586191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific peptides driving altered selection not identified\", \"Rat-specific allelic context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that natural TAP2 polymorphisms have limited functional impact and that viral inhibitors target TAP in a polymorphism-independent manner.\",\n      \"evidence\": \"Peptide transport and MHC class I assays across TAP1/TAP2 variant combinations with viral inhibitor testing\",\n      \"pmids\": [\"29879547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not address rare or disease-associated variants in depth\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the asymmetric NBD cycle is coupled mechanically to peptide translocation across the membrane, and the structural basis of TAP2 C-terminal selectivity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the translocation cycle in the timeline\", \"Residue-level selectivity determinants beyond residue 374 not mapped\", \"Full PLC architecture around TAP2 not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 4, 12]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 5, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 12]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"complexes\": [\n      \"TAP1/TAP2 transporter\",\n      \"MHC class I peptide-loading complex (PLC)\"\n    ],\n    \"partners\": [\n      \"TAP1\",\n      \"tapasin\",\n      \"calreticulin\",\n      \"MHC class I heavy chain\",\n      \"IRF-7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}