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Protein

HLA class II histocompatibility antigen, DRB1-3 chain

Gene

HLA-DRB1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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: UniProtKB

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: UniProtKB
  7. T cell costimulation Source: Reactome
  8. T cell receptor signaling pathway Source: Reactome
Complete GO annotation...

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.

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini30 – 227198ExtracellularSequence AnalysisAdd
BLAST
Transmembranei228 – 25023HelicalSequence AnalysisAdd
BLAST
Topological domaini251 – 26616CytoplasmicSequence AnalysisAdd
BLAST

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: UniProtKB
  9. plasma membrane Source: Reactome
  10. trans-Golgi network membrane Source: Reactome
  11. transport vesicle membrane Source: Reactome
Complete GO annotation...

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. 24 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 – 4711Combined sources
Turni48 – 514Combined sources
Beta strandi52 – 6110Combined sources
Beta strandi64 – 707Combined sources
Turni71 – 733Combined sources
Beta strandi75 – 806Combined sources
Helixi81 – 833Combined sources
Helixi84 – 929Combined sources
Helixi94 – 1018Combined sources
Helixi103 – 1064Combined sources
Helixi108 – 1158Combined sources
Turni116 – 1216Combined sources
Beta strandi127 – 1348Combined sources
Beta strandi138 – 1403Combined sources
Beta strandi143 – 1508Combined sources
Beta strandi152 – 1543Combined sources
Beta strandi157 – 1626Combined sources
Beta strandi180 – 1823Combined sources
Beta strandi184 – 1874Combined sources
Beta strandi189 – 1913Combined sources
Beta strandi199 – 2057Combined sources
Beta strandi213 – 2186Combined sources

3D structure databases

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

Miscellaneous databases

EvolutionaryTraceiP01912.

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.
OMAiNGTERRY.
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

        10         20         30         40         50
MVCLRLPGGS CMAVLTVTLM VLSSPLALAG DTRPRFLEYS TSECHFFNGT
60 70 80 90 100
ERVRYLDRYF HNQEENVRFD SDVGEFRAVT ELGRPDAEYW NSQKDLLEQK
110 120 130 140 150
RGRVDNYCRH NYGVVESFTV QRRVHPKVTV YPSKTQPLQH HNLLVCSVSG
160 170 180 190 200
FYPGSIEVRW FRNGQEEKTG VVSTGLIHNG DWTFQTLVML ETVPRSGEVY
210 220 230 240 250
TCQVEHPSVT SPLTVEWRAR SESAQSKMLS GVGGFVLGLL FLGAGLFIYF
260
RNQKGHSGLQ PRGFLS
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:
EMBLi
GenBanki
DDBJi
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.
ENST00000612249; ENSP00000479406; ENSG00000206306.
ENST00000621986; ENSP00000484489; ENSG00000206240.
GeneIDi3123.
KEGGihsa:3123.
UCSCiuc011eri.2. human.

Polymorphism databases

DMDMi1708116.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X00699 mRNA. Translation: CAA25295.1.
PIRiI37546. HLHU3D.
RefSeqiNP_001230894.1. NM_001243965.1.
UniGeneiHs.534322.
Hs.696211.
Hs.736560.

3D structure databases

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

Protein-protein interaction databases

BioGridi109368. 24 interactions.
DIPiDIP-6064N.
IntActiP01912. 8 interactions.
MINTiMINT-1505391.

Polymorphism databases

DMDMi1708116.

Proteomic databases

PRIDEiP01912.

Protocols and materials databases

DNASUi3123.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000328980; ENSP00000331343; ENSG00000206306.
ENST00000399450; ENSP00000382378; ENSG00000206240.
ENST00000612249; ENSP00000479406; ENSG00000206306.
ENST00000621986; ENSP00000484489; ENSG00000206240.
GeneIDi3123.
KEGGihsa:3123.
UCSCiuc011eri.2. human.

Organism-specific databases

CTDi3123.
GeneCardsiGC06M032546.
GC06Mj32477.
GC06Mn32480.
HGNCiHGNC:4948. HLA-DRB1.
MIMi142857. gene.
neXtProtiNX_P01912.
GenAtlasiSearch...

Phylogenomic databases

HOVERGENiHBG012730.
KOiK06752.
OMAiNGTERRY.
PhylomeDBiP01912.

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.

Miscellaneous databases

ChiTaRSiHLA-DRB1. human.
EvolutionaryTraceiP01912.
GenomeRNAii3123.
NextBioi12394.
SOURCEiSearch...

Gene expression databases

CleanExiHS_HLA-DRB1.
GenevestigatoriP01912.

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]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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: January 7, 2015
This is version 135 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.