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P01912

- 2B13_HUMAN

UniProt

P01912 - 2B13_HUMAN

Protein

HLA class II histocompatibility antigen, DRB1-3 chain

Gene

HLA-DRB1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 132 (01 Oct 2014)
      Sequence version 2 (01 Oct 1996)
      Previous versions | rss
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    Functioni

    Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route; where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules; and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments; exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides; autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs; other cells of the gastrointestinal tract; such as epithelial cells; express MHC class II molecules and CD74 and act as APCs; which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen; three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs; CD74 undergoes a sequential degradation by various proteases; including CTSS and CTSL; leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells; the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules; increased acidification produces increased proteolysis and efficient peptide loading.

    GO - Molecular functioni

    1. peptide antigen binding Source: UniProt

    GO - Biological processi

    1. antigen processing and presentation of exogenous peptide antigen via MHC class II Source: Reactome
    2. cytokine-mediated signaling pathway Source: Reactome
    3. humoral immune response mediated by circulating immunoglobulin Source: UniProtKB
    4. immunoglobulin production involved in immunoglobulin mediated immune response Source: UniProtKB
    5. interferon-gamma-mediated signaling pathway Source: Reactome
    6. peptide antigen assembly with MHC class II protein complex Source: UniProt
    7. T cell costimulation Source: Reactome
    8. T cell receptor signaling pathway Source: Reactome

    Keywords - Biological processi

    Immunity

    Enzyme and pathway databases

    ReactomeiREACT_121399. MHC class II antigen presentation.
    REACT_12555. Downstream TCR signaling.
    REACT_12582. Phosphorylation of CD3 and TCR zeta chains.
    REACT_12596. Translocation of ZAP-70 to Immunological synapse.
    REACT_12623. Generation of second messenger molecules.
    REACT_19324. PD-1 signaling.
    REACT_25078. Interferon gamma signaling.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    HLA class II histocompatibility antigen, DRB1-3 chain
    Alternative name(s):
    Clone P2-beta-3
    MHC class II antigen DRB1*3
    Gene namesi
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Unplaced

    Organism-specific databases

    HGNCiHGNC:4948. HLA-DRB1.

    Subcellular locationi

    Cell membrane 1 Publication; Single-pass type I membrane protein 1 Publication. Endoplasmic reticulum membrane 1 Publication; Single-pass type I membrane protein 1 Publication. Golgi apparatustrans-Golgi network membrane 1 Publication; Single-pass type I membrane protein 1 Publication. Endosome membrane 1 Publication; Single-pass type I membrane protein 1 Publication. Lysosome membrane 1 Publication; Single-pass type I membrane protein 1 Publication. Late endosome membrane 1 Publication; Single-pass type I membrane protein 1 Publication
    Note: The MHC class II complex transits through a number of intracellular compartments in the endocytic pathway until it reaches the cell membrane for antigen presentation.

    GO - Cellular componenti

    1. clathrin-coated endocytic vesicle membrane Source: Reactome
    2. endocytic vesicle membrane Source: Reactome
    3. ER to Golgi transport vesicle membrane Source: Reactome
    4. Golgi membrane Source: Reactome
    5. integral component of lumenal side of endoplasmic reticulum membrane Source: Reactome
    6. late endosome membrane Source: UniProtKB
    7. lysosomal membrane Source: UniProtKB
    8. MHC class II protein complex Source: UniProt
    9. plasma membrane Source: Reactome
    10. trans-Golgi network membrane Source: Reactome
    11. transport vesicle membrane Source: Reactome

    Keywords - Cellular componenti

    Cell membrane, Endoplasmic reticulum, Endosome, Golgi apparatus, Lysosome, Membrane, MHC II

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 2929Add
    BLAST
    Chaini30 – 266237HLA class II histocompatibility antigen, DRB1-3 chainPRO_0000018965Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi44 ↔ 1081 PublicationPROSITE-ProRule annotation
    Glycosylationi48 – 481N-linked (GlcNAc...)1 Publication
    Disulfide bondi146 ↔ 2021 PublicationPROSITE-ProRule annotation
    Cross-linki254 – 254Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity

    Post-translational modificationi

    Ubiquitinated by MARCH1 and MARCH8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.1 Publication

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Isopeptide bond, Ubl conjugation

    Proteomic databases

    PRIDEiP01912.

    Expressioni

    Gene expression databases

    CleanExiHS_HLA-DRB1.
    GenevestigatoriP01912.

    Interactioni

    Subunit structurei

    Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.1 Publication

    Protein-protein interaction databases

    BioGridi109368. 15 interactions.
    DIPiDIP-6064N.
    IntActiP01912. 8 interactions.
    MINTiMINT-1505391.

    Structurei

    Secondary structure

    1
    266
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi37 – 4711
    Turni48 – 514
    Beta strandi52 – 6110
    Beta strandi64 – 707
    Turni71 – 733
    Beta strandi75 – 806
    Helixi81 – 833
    Helixi84 – 929
    Helixi94 – 1018
    Helixi103 – 1064
    Helixi108 – 1158
    Turni116 – 1216
    Beta strandi127 – 1348
    Beta strandi138 – 1403
    Beta strandi143 – 1508
    Beta strandi152 – 1543
    Beta strandi157 – 1626
    Beta strandi180 – 1823
    Beta strandi184 – 1874
    Beta strandi189 – 1913
    Beta strandi199 – 2057
    Beta strandi213 – 2186

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1A6AX-ray2.75B34-220[»]
    ProteinModelPortaliP01912.
    SMRiP01912. Positions 34-220.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP01912.

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini30 – 227198ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini251 – 26616CytoplasmicSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei228 – 25023HelicalSequence AnalysisAdd
    BLAST

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini126 – 21489Ig-like C1-typeAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni30 – 12394Beta-1Add
    BLAST
    Regioni124 – 21794Beta-2Add
    BLAST
    Regioni218 – 22710Connecting peptide

    Sequence similaritiesi

    Belongs to the MHC class II family.Curated

    Keywords - Domaini

    Signal, Transmembrane, Transmembrane helix

    Phylogenomic databases

    HOVERGENiHBG012730.
    KOiK06752.
    OMAiNGMERVR.
    PhylomeDBiP01912.

    Family and domain databases

    Gene3Di2.60.40.10. 1 hit.
    3.10.320.10. 1 hit.
    InterProiIPR007110. Ig-like_dom.
    IPR013783. Ig-like_fold.
    IPR003006. Ig/MHC_CS.
    IPR003597. Ig_C1-set.
    IPR011162. MHC_I/II-like_Ag-recog.
    IPR014745. MHC_II_a/b_N.
    IPR000353. MHC_II_b_N.
    [Graphical view]
    PfamiPF07654. C1-set. 1 hit.
    PF00969. MHC_II_beta. 1 hit.
    [Graphical view]
    ProDomiPD000328. MHC_II_b_N. 1 hit.
    [Graphical view] [Entries sharing at least one domain]
    SMARTiSM00407. IGc1. 1 hit.
    SM00921. MHC_II_beta. 1 hit.
    [Graphical view]
    SUPFAMiSSF54452. SSF54452. 1 hit.
    PROSITEiPS50835. IG_LIKE. 1 hit.
    PS00290. IG_MHC. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P01912-1 [UniParc]FASTAAdd to Basket

    « Hide

    MVCLRLPGGS CMAVLTVTLM VLSSPLALAG DTRPRFLEYS TSECHFFNGT    50
    ERVRYLDRYF HNQEENVRFD SDVGEFRAVT ELGRPDAEYW NSQKDLLEQK 100
    RGRVDNYCRH NYGVVESFTV QRRVHPKVTV YPSKTQPLQH HNLLVCSVSG 150
    FYPGSIEVRW FRNGQEEKTG VVSTGLIHNG DWTFQTLVML ETVPRSGEVY 200
    TCQVEHPSVT SPLTVEWRAR SESAQSKMLS GVGGFVLGLL FLGAGLFIYF 250
    RNQKGHSGLQ PRGFLS 266
    Length:266
    Mass (Da):30,120
    Last modified:October 1, 1996 - v2
    Checksum:i37329B097C6BEEB4
    GO

    Polymorphismi

    The following alleles of DRB1-3 are known: DRB1*03:01; DRB1*03:02; DRB1*03:03; DRB1*03:04; DRB1*03:05; DRB1*03:06; DRB1*03:07; DRB1*03:08; DRB1*03:09; DRB1*03:10; DRB1*03:11; DRB1*03:12; DRB1*03:13; DRB1*03:14; DRB1*03:15; DRB1*03:16; DRB1*03:17; DRB1*03:18; DRB1*03:19; DRB1*03:20; DRB1*03:21; DRB1*03:22; DRB1*03:23; DRB1*03:24; DRB1*03:25; DRB1*03:26; DRB1*03:27; DRB1*03:28; DRB1*03:29; DRB1*03:30; DRB1*03:31; DRB1*03:32; DRB1*03:33; DRB1*03:34; DRB1*03:35; DRB1*03:36; DRB1*03:37; DRB1*03:38; DRB1*03:39; DRB1*03:40 and DRB1*03:41. The sequence shown is that of DRB1*03:01.

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti55 – 551Y → F.
    Corresponds to variant rs16822516 [ dbSNP | Ensembl ].
    VAR_050371
    Natural varianti106 – 1061N → T.
    Corresponds to variant rs9269941 [ dbSNP | Ensembl ].
    VAR_050372
    Natural varianti164 – 1641G → S.
    Corresponds to variant rs1059633 [ dbSNP | Ensembl ].
    VAR_050373
    Natural varianti169 – 1691T → A.
    Corresponds to variant rs2308768 [ dbSNP | Ensembl ].
    VAR_050374
    Natural varianti236 – 2361V → M.
    Corresponds to variant rs2230816 [ dbSNP | Ensembl ].
    VAR_056545

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X00699 mRNA. Translation: CAA25295.1.
    PIRiI37546. HLHU3D.
    RefSeqiNP_001230894.1. NM_001243965.1.
    UniGeneiHs.534322.
    Hs.696211.
    Hs.736560.

    Genome annotation databases

    EnsembliENST00000328980; ENSP00000331343; ENSG00000206306.
    ENST00000399450; ENSP00000382378; ENSG00000206240.
    GeneIDi3123.
    KEGGihsa:3123.
    UCSCiuc011eri.2. human.

    Polymorphism databases

    DMDMi1708116.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X00699 mRNA. Translation: CAA25295.1 .
    PIRi I37546. HLHU3D.
    RefSeqi NP_001230894.1. NM_001243965.1.
    UniGenei Hs.534322.
    Hs.696211.
    Hs.736560.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1A6A X-ray 2.75 B 34-220 [» ]
    ProteinModelPortali P01912.
    SMRi P01912. Positions 34-220.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 109368. 15 interactions.
    DIPi DIP-6064N.
    IntActi P01912. 8 interactions.
    MINTi MINT-1505391.

    Polymorphism databases

    DMDMi 1708116.

    Proteomic databases

    PRIDEi P01912.

    Protocols and materials databases

    DNASUi 3123.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000328980 ; ENSP00000331343 ; ENSG00000206306 .
    ENST00000399450 ; ENSP00000382378 ; ENSG00000206240 .
    GeneIDi 3123.
    KEGGi hsa:3123.
    UCSCi uc011eri.2. human.

    Organism-specific databases

    CTDi 3123.
    GeneCardsi GC06M032546.
    GC06Mj32477.
    GC06Mn32480.
    HGNCi HGNC:4948. HLA-DRB1.
    MIMi 142857. gene.
    neXtProti NX_P01912.
    GenAtlasi Search...

    Phylogenomic databases

    HOVERGENi HBG012730.
    KOi K06752.
    OMAi NGMERVR.
    PhylomeDBi P01912.

    Enzyme and pathway databases

    Reactomei REACT_121399. MHC class II antigen presentation.
    REACT_12555. Downstream TCR signaling.
    REACT_12582. Phosphorylation of CD3 and TCR zeta chains.
    REACT_12596. Translocation of ZAP-70 to Immunological synapse.
    REACT_12623. Generation of second messenger molecules.
    REACT_19324. PD-1 signaling.
    REACT_25078. Interferon gamma signaling.

    Miscellaneous databases

    ChiTaRSi HLA-DRB1. human.
    EvolutionaryTracei P01912.
    GenomeRNAii 3123.
    NextBioi 12394.
    SOURCEi Search...

    Gene expression databases

    CleanExi HS_HLA-DRB1.
    Genevestigatori P01912.

    Family and domain databases

    Gene3Di 2.60.40.10. 1 hit.
    3.10.320.10. 1 hit.
    InterProi IPR007110. Ig-like_dom.
    IPR013783. Ig-like_fold.
    IPR003006. Ig/MHC_CS.
    IPR003597. Ig_C1-set.
    IPR011162. MHC_I/II-like_Ag-recog.
    IPR014745. MHC_II_a/b_N.
    IPR000353. MHC_II_b_N.
    [Graphical view ]
    Pfami PF07654. C1-set. 1 hit.
    PF00969. MHC_II_beta. 1 hit.
    [Graphical view ]
    ProDomi PD000328. MHC_II_b_N. 1 hit.
    [Graphical view ] [Entries sharing at least one domain ]
    SMARTi SM00407. IGc1. 1 hit.
    SM00921. MHC_II_beta. 1 hit.
    [Graphical view ]
    SUPFAMi SSF54452. SSF54452. 1 hit.
    PROSITEi PS50835. IG_LIKE. 1 hit.
    PS00290. IG_MHC. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Mutations and selection in the generation of class II histocompatibility antigen polymorphism."
      Peterson P.A., Gustafsson K., Wiman K.G., Emmoth E., Larhammar D., Boehme J., Hyldig-Nielsen J.J., Ronne H., Rask L.
      EMBO J. 3:1655-1660(1984) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ALLELE DRB1*03:01).
    2. Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 30-266 (ALLELE DRB1*03:01).
    3. "Invariant chain structure and MHC class II function."
      Cresswell P.
      Cell 84:505-507(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.
    4. "Presentation of antigens by MHC class II molecules: getting the most out of them."
      Villadangos J.A.
      Mol. Immunol. 38:329-346(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.
    5. "Autophagy in MHC class II presentation: sampling from within."
      Menendez-Benito V., Neefjes J.
      Immunity 26:1-3(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.
    6. "MHC class II molecules on the move for successful antigen presentation."
      Rocha N., Neefjes J.
      EMBO J. 27:1-5(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.
    7. "MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation."
      De Gassart A., Camosseto V., Thibodeau J., Ceppi M., Catalan N., Pierre P., Gatti E.
      Proc. Natl. Acad. Sci. U.S.A. 105:3491-3496(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION BY MARCH1, SUBCELLULAR LOCATION.
    8. "MHC class II transport at a glance."
      Berger A.C., Roche P.A.
      J. Cell Sci. 122:1-4(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.
    9. "CD74 in antigen presentation, inflammation, and cancers of the gastrointestinal tract."
      Beswick E.J., Reyes V.E.
      World J. Gastroenterol. 15:2855-2861(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW.
    10. "Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry."
      Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.
      J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-48.
      Tissue: Liver.
    11. "The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3."
      Ghosh P., Amaya M., Mellins E., Wiley D.C.
      Nature 378:457-462(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF 34-220 OF HLA-DRA/HLA-DRB1 HETERODIMER IN COMPLEX WITH CD74 PEPTIDE (CLIP), SUBUNIT, DISULFIDE BONDS.

    Entry informationi

    Entry namei2B13_HUMAN
    AccessioniPrimary (citable) accession number: P01912
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 21, 1986
    Last sequence update: October 1, 1996
    Last modified: October 1, 2014
    This is version 132 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 6
      Human chromosome 6: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3