{"gene":"HLA-DMB","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1996,"finding":"A tyrosine-based tetrapeptide motif in the cytoplasmic domain of HLA-DMB is necessary and sufficient for targeting to late endocytic/lysosomal compartments (MIICs); mutation of the tyrosine to alanine redirects the protein to the cell surface. Correct intracellular targeting of HLA-DM to these compartments is required for normal antigen-presentation function in B cells.","method":"CD8-DMB chimeric hybrid molecules expressed in HeLa cells; tyrosine-to-alanine point mutagenesis; immunoelectron microscopy on ultrathin cryosections; co-transfection with HLA-DR and invariant chain","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of targeting signal combined with direct localization by immuno-EM and functional readout in B cells; multiple orthogonal methods in a single study","pmids":["8757605"],"is_preprint":false},{"year":1995,"finding":"Loss-of-function mutations in HLA-DMB (a C→T point mutation introducing a cryptic splice site in exon 3, or a G→A mutation in exon 3 causing skipping of exon 4) result in abnormal DMB transcripts and defective MHC class II antigen presentation in B lymphoblastoid cell lines, establishing that intact DMB is required for the antigen-presentation function of conventional MHC class II molecules.","method":"Sequencing of DMB mutants in presentation-defective B-LCL lines; genomic mapping of DMB intron/exon boundaries; RT-PCR characterization of aberrant transcripts","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function mutant analysis with defined molecular lesions and cellular phenotype, single lab","pmids":["7528727"],"is_preprint":false},{"year":1994,"finding":"HLA-DMB has a six-exon genomic structure typical of MHC class II beta genes, but with one extra codon in exon 3 (membrane-proximal domain) compared to other class II alpha genes, and its gene organization is conserved with other class II families, consistent with an ancient divergence from classical class II genes.","method":"Genomic nucleotide sequencing and comparative exon-intron boundary analysis of HLA-DMA and HLA-DMB","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — direct genomic sequencing and structural characterization, single lab","pmids":["8034636"],"is_preprint":false},{"year":1997,"finding":"CIITA activates the HLA-DMB promoter through its C-terminal 41 amino acids; deletion of this region abolishes DMB promoter activation, and C-terminal deletion mutants of CIITA act as transdominant negatives to suppress endogenous CIITA-driven DMB expression.","method":"Transfection of CIITA C-terminal deletion mutants; DMB promoter reporter assays; transdominant-negative assay in cells with endogenous CIITA","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — deletion mutagenesis with promoter reporter and transdominant suppression assay; single lab, multiple constructs","pmids":["9300700"],"is_preprint":false},{"year":1999,"finding":"HLA-DMB mRNA and protein are expressed in untransformed thyrocytes, and CIITA expression (induced by IFN-γ) precedes and is required for upregulation of DMB, invariant chain, and DRA, placing CIITA upstream of DMB in the antigen-processing pathway in non-professional APCs.","method":"RT-PCR and western blot for HLA-DMB, CIITA, Ii, and DRA in IFN-γ-treated thyrocytes; temporal expression analysis","journal":"Clinical and experimental immunology","confidence":"Low","confidence_rationale":"Tier 3 — expression time-course providing pathway ordering inference, single lab, no direct functional perturbation of DMB","pmids":["10209506"],"is_preprint":false}],"current_model":"HLA-DMB (the beta chain of the non-classical MHC class II heterodimer HLA-DM) is targeted to late endosomal/lysosomal MHC class II compartments (MIICs) via a tyrosine-based motif in its cytoplasmic tail, where it is required for efficient peptide loading onto classical MHC class II molecules; its expression is transcriptionally driven by CIITA acting through the DMB promoter, and loss-of-function mutations in DMB cause defective antigen presentation."},"narrative":{"teleology":[{"year":1994,"claim":"Defining the genomic architecture of HLA-DMB established it as a bona fide but divergent MHC class II beta gene, providing a structural framework for subsequent functional studies.","evidence":"Genomic nucleotide sequencing and exon-intron boundary analysis of HLA-DMB","pmids":["8034636"],"confidence":"Medium","gaps":["No functional data on DMB protein activity at this stage","Relationship to peptide loading on classical MHC class II not addressed"]},{"year":1995,"claim":"Identification of loss-of-function mutations in DMB in presentation-defective B-cell lines demonstrated that intact DMB is essential for MHC class II antigen presentation, linking the gene to a cellular function rather than mere sequence homology.","evidence":"Sequencing and RT-PCR of DMB mutants in antigen-presentation-defective B-LCL lines","pmids":["7528727"],"confidence":"Medium","gaps":["Rescue by wild-type DMB re-expression not shown in this study","Mechanism by which DMB promotes antigen presentation (e.g., peptide exchange catalysis) not determined","Single laboratory observation"]},{"year":1996,"claim":"Mutagenesis and immuno-EM revealed that a cytoplasmic tyrosine-based motif directs HLA-DMB to late endosomal/lysosomal MIICs, and that correct subcellular targeting is required for antigen-presentation function, establishing the trafficking mechanism.","evidence":"CD8-DMB chimera expression in HeLa cells; Tyr→Ala mutagenesis; immunoelectron microscopy; functional assay in B cells","pmids":["8757605"],"confidence":"High","gaps":["Adaptor protein(s) recognizing the tyrosine motif not identified","Whether DMA contributes to targeting independently of DMB not resolved"]},{"year":1997,"claim":"Deletion mutagenesis of CIITA showed that its C-terminal 41 amino acids are required for DMB promoter activation, defining the transcriptional control mechanism upstream of DMB expression.","evidence":"CIITA C-terminal deletion mutants with DMB promoter reporter assays and transdominant-negative suppression","pmids":["9300700"],"confidence":"Medium","gaps":["Direct binding of CIITA to the DMB promoter not demonstrated","Whether CIITA acts through the same promoter elements as for classical MHC II genes not resolved"]},{"year":null,"claim":"The precise catalytic mechanism by which HLA-DM (DMB with DMA) facilitates peptide exchange on classical MHC class II molecules, and the identity of the adaptor(s) that recognize the DMB cytoplasmic tyrosine motif for endosomal sorting, remain to be mechanistically defined by direct biochemical or structural evidence in the timeline.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of DM-mediated peptide exchange captured in this timeline","Adaptor proteins binding the DMB tyrosine motif not identified","Relative contribution of DMB vs DMA subunit to catalytic peptide-editing activity not dissected"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]}],"complexes":["HLA-DM (DMA/DMB heterodimer)"],"partners":["HLA-DMA","CIITA"],"other_free_text":[]},"mechanistic_narrative":"HLA-DMB encodes the beta chain of the non-classical MHC class II heterodimer HLA-DM, which resides in late endosomal/lysosomal MHC class II compartments (MIICs) and is required for efficient peptide loading onto classical MHC class II molecules and normal antigen presentation [PMID:8757605, PMID:7528727]. A tyrosine-based tetrapeptide motif in the HLA-DMB cytoplasmic tail is necessary and sufficient for targeting to MIICs; mutation of this tyrosine redirects the protein to the cell surface and impairs antigen-presentation function [PMID:8757605]. Transcription of DMB is driven by the MHC class II transactivator CIITA, whose C-terminal 41 amino acids are essential for DMB promoter activation, and loss-of-function mutations in DMB that produce aberrant transcripts abolish MHC class II-restricted antigen presentation [PMID:9300700, PMID:7528727]."},"prefetch_data":{"uniprot":{"accession":"P28068","full_name":"HLA class II histocompatibility antigen, DM beta chain","aliases":["MHC class II antigen DMB","Really interesting new gene 7 protein"],"length_aa":263,"mass_kda":28.9,"function":"Plays a critical role in catalyzing the release of class II-associated invariant chain peptide (CLIP) from newly synthesized MHC class II molecules and freeing the peptide binding site for acquisition of antigenic peptides. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO","subcellular_location":"Late endosome membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/P28068/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HLA-DMB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HLA-DMB","total_profiled":1310},"omim":[{"mim_id":"142920","title":"HLA-DO HISTOCOMPATIBILITY TYPE; HLA-DO","url":"https://www.omim.org/entry/142920"},{"mim_id":"142856","title":"MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS II, DM BETA; HLA-DMB","url":"https://www.omim.org/entry/142856"},{"mim_id":"142855","title":"MAJOR HISTOCOMPATIBILITY COMPLEX, CLASS II, DM ALPHA; HLA-DMA","url":"https://www.omim.org/entry/142855"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":76.7},{"tissue":"lymphoid tissue","ntpm":100.7}],"url":"https://www.proteinatlas.org/search/HLA-DMB"},"hgnc":{"alias_symbol":["D6S221E","RING7"],"prev_symbol":[]},"alphafold":{"accession":"P28068","domains":[{"cath_id":"3.10.320.10","chopping":"21-99","consensus_level":"high","plddt":95.1018,"start":21,"end":99},{"cath_id":"2.60.40.10","chopping":"115-206","consensus_level":"high","plddt":94.7439,"start":115,"end":206}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P28068","model_url":"https://alphafold.ebi.ac.uk/files/AF-P28068-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P28068-F1-predicted_aligned_error_v6.png","plddt_mean":89.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HLA-DMB","jax_strain_url":"https://www.jax.org/strain/search?query=HLA-DMB"},"sequence":{"accession":"P28068","fasta_url":"https://rest.uniprot.org/uniprotkb/P28068.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P28068/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P28068"}},"corpus_meta":[{"pmid":"8034636","id":"PMC_8034636","title":"Genomic organization of HLA-DMA and HLA-DMB. Comparison of the gene organization of all six class II families in the human major histocompatibility complex.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8034636","citation_count":42,"is_preprint":false},{"pmid":"8757605","id":"PMC_8757605","title":"Targeting signal and subcellular compartments involved in the intracellular trafficking of HLA-DMB.","date":"1996","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8757605","citation_count":28,"is_preprint":false},{"pmid":"9300700","id":"PMC_9300700","title":"Activation and transdominant suppression of MHC class II and HLA-DMB promoters by a series of C-terminal class II transactivator deletion mutants.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9300700","citation_count":26,"is_preprint":false},{"pmid":"10209506","id":"PMC_10209506","title":"HLA-DMB expression by thyrocytes: indication of the antigen-processing and possible presenting capability of thyroid cells.","date":"1999","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10209506","citation_count":21,"is_preprint":false},{"pmid":"8813742","id":"PMC_8813742","title":"Analysis on allelic variation of the HLA-DMB gene in Japanese by PCR-RFLP as well as direct DNA sequencing and identification of a new DMB allele, DMB*0105.","date":"1996","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/8813742","citation_count":21,"is_preprint":false},{"pmid":"25008864","id":"PMC_25008864","title":"SNP screening of central MHC-identified HLA-DMB as a candidate susceptibility gene for HIV-related Kaposi's sarcoma.","date":"2014","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/25008864","citation_count":17,"is_preprint":false},{"pmid":"10527398","id":"PMC_10527398","title":"HLA-DMB gene and HLA-DRA promoter region polymorphisms in Australian multiple sclerosis patients.","date":"1999","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10527398","citation_count":15,"is_preprint":false},{"pmid":"7528727","id":"PMC_7528727","title":"Analysis of HLA-DMB mutants and -DMB genomic structure.","date":"1995","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/7528727","citation_count":9,"is_preprint":false},{"pmid":"8045787","id":"PMC_8045787","title":"Cloning of the region between HLA-DMB and LMP2 in the human major histocompatibility complex.","date":"1994","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8045787","citation_count":6,"is_preprint":false},{"pmid":"40347049","id":"PMC_40347049","title":"Extensive Analysis of Genetic Diversity in HLA-DMA, HLA-DMB, HLA-DOA and HLA-DOB: Characterisation of 236 Novel Alleles.","date":"2025","source":"HLA","url":"https://pubmed.ncbi.nlm.nih.gov/40347049","citation_count":5,"is_preprint":false},{"pmid":"26944519","id":"PMC_26944519","title":"HLA-DMB in Amerindians: Specific linkage of DMB*01:03:01/DRB1 alleles.","date":"2016","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26944519","citation_count":2,"is_preprint":false},{"pmid":"36870854","id":"PMC_36870854","title":"HLA-DMB alleles and haplotypes in Ecuador (Cuenca) Amerindians: Importance for HLA and disease studies.","date":"2023","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36870854","citation_count":1,"is_preprint":false},{"pmid":"16737583","id":"PMC_16737583","title":"[Relationship of trichloroethylene-induced medicamentosa like dermatitis to HLA-DMA and HLA-DMB].","date":"2006","source":"Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases","url":"https://pubmed.ncbi.nlm.nih.gov/16737583","citation_count":1,"is_preprint":false},{"pmid":"40267082","id":"PMC_40267082","title":"Methylome and transcriptome analyses reveal HLA-DMB's contribution to periodontitis development.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/40267082","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.17.24315623","title":"Identification of Shared and Unique Key Biomarkers of Alcohol Liver Cirrhosis and Non-Alcoholic Steatohepatitis Through Machine Learning Network-Based Algorithms","date":"2024-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.17.24315623","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.23.25330155","title":"Immune, Developmental, and Synaptic Pathways Define Bipolar Disorder Clinical Heterogeneity","date":"2025-06-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.23.25330155","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9475,"output_tokens":1322,"usd":0.024127},"stage2":{"model":"claude-opus-4-6","input_tokens":4552,"output_tokens":1348,"usd":0.08469},"total_usd":0.108817,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"A tyrosine-based tetrapeptide motif in the cytoplasmic domain of HLA-DMB is necessary and sufficient for targeting to late endocytic/lysosomal compartments (MIICs); mutation of the tyrosine to alanine redirects the protein to the cell surface. Correct intracellular targeting of HLA-DM to these compartments is required for normal antigen-presentation function in B cells.\",\n      \"method\": \"CD8-DMB chimeric hybrid molecules expressed in HeLa cells; tyrosine-to-alanine point mutagenesis; immunoelectron microscopy on ultrathin cryosections; co-transfection with HLA-DR and invariant chain\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of targeting signal combined with direct localization by immuno-EM and functional readout in B cells; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"8757605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Loss-of-function mutations in HLA-DMB (a C→T point mutation introducing a cryptic splice site in exon 3, or a G→A mutation in exon 3 causing skipping of exon 4) result in abnormal DMB transcripts and defective MHC class II antigen presentation in B lymphoblastoid cell lines, establishing that intact DMB is required for the antigen-presentation function of conventional MHC class II molecules.\",\n      \"method\": \"Sequencing of DMB mutants in presentation-defective B-LCL lines; genomic mapping of DMB intron/exon boundaries; RT-PCR characterization of aberrant transcripts\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mutant analysis with defined molecular lesions and cellular phenotype, single lab\",\n      \"pmids\": [\"7528727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"HLA-DMB has a six-exon genomic structure typical of MHC class II beta genes, but with one extra codon in exon 3 (membrane-proximal domain) compared to other class II alpha genes, and its gene organization is conserved with other class II families, consistent with an ancient divergence from classical class II genes.\",\n      \"method\": \"Genomic nucleotide sequencing and comparative exon-intron boundary analysis of HLA-DMA and HLA-DMB\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct genomic sequencing and structural characterization, single lab\",\n      \"pmids\": [\"8034636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CIITA activates the HLA-DMB promoter through its C-terminal 41 amino acids; deletion of this region abolishes DMB promoter activation, and C-terminal deletion mutants of CIITA act as transdominant negatives to suppress endogenous CIITA-driven DMB expression.\",\n      \"method\": \"Transfection of CIITA C-terminal deletion mutants; DMB promoter reporter assays; transdominant-negative assay in cells with endogenous CIITA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — deletion mutagenesis with promoter reporter and transdominant suppression assay; single lab, multiple constructs\",\n      \"pmids\": [\"9300700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HLA-DMB mRNA and protein are expressed in untransformed thyrocytes, and CIITA expression (induced by IFN-γ) precedes and is required for upregulation of DMB, invariant chain, and DRA, placing CIITA upstream of DMB in the antigen-processing pathway in non-professional APCs.\",\n      \"method\": \"RT-PCR and western blot for HLA-DMB, CIITA, Ii, and DRA in IFN-γ-treated thyrocytes; temporal expression analysis\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression time-course providing pathway ordering inference, single lab, no direct functional perturbation of DMB\",\n      \"pmids\": [\"10209506\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HLA-DMB (the beta chain of the non-classical MHC class II heterodimer HLA-DM) is targeted to late endosomal/lysosomal MHC class II compartments (MIICs) via a tyrosine-based motif in its cytoplasmic tail, where it is required for efficient peptide loading onto classical MHC class II molecules; its expression is transcriptionally driven by CIITA acting through the DMB promoter, and loss-of-function mutations in DMB cause defective antigen presentation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HLA-DMB encodes the beta chain of the non-classical MHC class II heterodimer HLA-DM, which resides in late endosomal/lysosomal MHC class II compartments (MIICs) and is required for efficient peptide loading onto classical MHC class II molecules and normal antigen presentation [PMID:8757605, PMID:7528727]. A tyrosine-based tetrapeptide motif in the HLA-DMB cytoplasmic tail is necessary and sufficient for targeting to MIICs; mutation of this tyrosine redirects the protein to the cell surface and impairs antigen-presentation function [PMID:8757605]. Transcription of DMB is driven by the MHC class II transactivator CIITA, whose C-terminal 41 amino acids are essential for DMB promoter activation, and loss-of-function mutations in DMB that produce aberrant transcripts abolish MHC class II-restricted antigen presentation [PMID:9300700, PMID:7528727].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Defining the genomic architecture of HLA-DMB established it as a bona fide but divergent MHC class II beta gene, providing a structural framework for subsequent functional studies.\",\n      \"evidence\": \"Genomic nucleotide sequencing and exon-intron boundary analysis of HLA-DMB\",\n      \"pmids\": [\"8034636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional data on DMB protein activity at this stage\",\n        \"Relationship to peptide loading on classical MHC class II not addressed\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of loss-of-function mutations in DMB in presentation-defective B-cell lines demonstrated that intact DMB is essential for MHC class II antigen presentation, linking the gene to a cellular function rather than mere sequence homology.\",\n      \"evidence\": \"Sequencing and RT-PCR of DMB mutants in antigen-presentation-defective B-LCL lines\",\n      \"pmids\": [\"7528727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Rescue by wild-type DMB re-expression not shown in this study\",\n        \"Mechanism by which DMB promotes antigen presentation (e.g., peptide exchange catalysis) not determined\",\n        \"Single laboratory observation\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mutagenesis and immuno-EM revealed that a cytoplasmic tyrosine-based motif directs HLA-DMB to late endosomal/lysosomal MIICs, and that correct subcellular targeting is required for antigen-presentation function, establishing the trafficking mechanism.\",\n      \"evidence\": \"CD8-DMB chimera expression in HeLa cells; Tyr→Ala mutagenesis; immunoelectron microscopy; functional assay in B cells\",\n      \"pmids\": [\"8757605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Adaptor protein(s) recognizing the tyrosine motif not identified\",\n        \"Whether DMA contributes to targeting independently of DMB not resolved\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Deletion mutagenesis of CIITA showed that its C-terminal 41 amino acids are required for DMB promoter activation, defining the transcriptional control mechanism upstream of DMB expression.\",\n      \"evidence\": \"CIITA C-terminal deletion mutants with DMB promoter reporter assays and transdominant-negative suppression\",\n      \"pmids\": [\"9300700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding of CIITA to the DMB promoter not demonstrated\",\n        \"Whether CIITA acts through the same promoter elements as for classical MHC II genes not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise catalytic mechanism by which HLA-DM (DMB with DMA) facilitates peptide exchange on classical MHC class II molecules, and the identity of the adaptor(s) that recognize the DMB cytoplasmic tyrosine motif for endosomal sorting, remain to be mechanistically defined by direct biochemical or structural evidence in the timeline.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of DM-mediated peptide exchange captured in this timeline\",\n        \"Adaptor proteins binding the DMB tyrosine motif not identified\",\n        \"Relative contribution of DMB vs DMA subunit to catalytic peptide-editing activity not dissected\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"HLA-DM (DMA/DMB heterodimer)\"],\n    \"partners\": [\"HLA-DMA\", \"CIITA\"],\n    \"other_free_text\": []\n  }\n}\n```"}