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Protein

HLA class II histocompatibility antigen, DRB1-4 beta 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

  • MHC class II receptor activity Source: UniProtKB
  • peptide antigen binding Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Immunity

Enzyme and pathway databases

BioCyciZFISH:G66-31956-MONOMER.
ReactomeiR-HSA-202424. Downstream TCR signaling.
R-HSA-202427. Phosphorylation of CD3 and TCR zeta chains.
R-HSA-202430. Translocation of ZAP-70 to Immunological synapse.
R-HSA-202433. Generation of second messenger molecules.
R-HSA-2132295. MHC class II antigen presentation.
R-HSA-389948. PD-1 signaling.
R-HSA-877300. Interferon gamma signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
HLA class II histocompatibility antigen, DRB1-4 beta chain
Alternative name(s):
MHC class II antigen DRB1*4
Short name:
DR-4
Short name:
DR4
Gene namesi
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

HGNCiHGNC:4948. HLA-DRB1.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini30 – 227ExtracellularSequence analysisAdd BLAST198
Transmembranei228 – 250HelicalSequence analysisAdd BLAST23
Topological domaini251 – 266CytoplasmicSequence analysisAdd BLAST16

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

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

Pathology & Biotechi

Organism-specific databases

MalaCardsiHLA-DRB1.

Polymorphism and mutation databases

DMDMi122253.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 29Add BLAST29
ChainiPRO_000001895030 – 266HLA class II histocompatibility antigen, DRB1-4 beta chainAdd BLAST237

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi44 ↔ 108PROSITE-ProRule annotation
Glycosylationi48N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi146 ↔ 202PROSITE-ProRule annotation
Cross-linki254Glycyl 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

EPDiP13760.
MaxQBiP13760.
PeptideAtlasiP13760.
PRIDEiP13760.

PTM databases

iPTMnetiP13760.
PhosphoSitePlusiP13760.

Expressioni

Gene expression databases

BgeeiENSG00000228080.
CleanExiHS_HLA-DRB1.

Organism-specific databases

HPAiHPA043151.

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.

Protein-protein interaction databases

IntActiP13760. 6 interactors.

Structurei

Secondary structure

1266
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi36 – 47Combined sources12
Turni48 – 51Combined sources4
Beta strandi52 – 61Combined sources10
Beta strandi64 – 70Combined sources7
Turni71 – 73Combined sources3
Beta strandi74 – 80Combined sources7
Helixi81 – 83Combined sources3
Helixi84 – 91Combined sources8
Helixi94 – 106Combined sources13
Helixi108 – 115Combined sources8
Helixi116 – 118Combined sources3
Turni119 – 121Combined sources3
Beta strandi127 – 133Combined sources7
Beta strandi143 – 154Combined sources12
Beta strandi157 – 162Combined sources6
Beta strandi165 – 167Combined sources3
Beta strandi171 – 173Combined sources3
Beta strandi180 – 182Combined sources3
Beta strandi184 – 191Combined sources8
Beta strandi199 – 205Combined sources7
Beta strandi213 – 218Combined sources6

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1D5MX-ray2.00B30-221[»]
1D5XX-ray2.45B30-221[»]
1D5ZX-ray2.00B30-221[»]
1D6EX-ray2.45B30-221[»]
1J8HX-ray2.40B30-221[»]
2SEBX-ray2.50B30-221[»]
3O6FX-ray2.80B/F31-221[»]
3T0EX-ray4.00B30-221[»]
4IS6X-ray2.50B30-221[»]
4MCYX-ray2.30B30-219[»]
4MCZX-ray2.41B30-219[»]
4MD0X-ray2.19B30-219[»]
4MD4X-ray1.95B30-219[»]
4MD5X-ray1.65B30-219[»]
4MDIX-ray2.00B30-219[»]
4MDJX-ray1.70B30-219[»]
4Y19X-ray2.50B30-219[»]
4Y1AX-ray4.00B30-219[»]
ProteinModelPortaliP13760.
SMRiP13760.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP13760.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini126 – 214Ig-like C1-typeAdd BLAST89

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni30 – 124Beta-1Add BLAST95
Regioni125 – 227Beta-2Add BLAST103

Sequence similaritiesi

Belongs to the MHC class II family.Curated

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

HOVERGENiHBG012730.
PhylomeDBiP13760.

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]
SUPFAMiSSF48726. SSF48726. 1 hit.
SSF54452. 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.

P13760-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MVCLKFPGGS CMAALTVTLM VLSSPLALAG DTRPRFLEQV KHECHFFNGT
60 70 80 90 100
ERVRFLDRYF YHQEEYVRFD SDVGEYRAVT ELGRPDAEYW NSQKDLLEQK
110 120 130 140 150
RAAVDTYCRH NYGVGESFTV QRRVYPEVTV YPAKTQPLQH HNLLVCSVNG
160 170 180 190 200
FYPGSIEVRW FRNGQEEKTG VVSTGLIQNG DWTFQTLVML ETVPRSGEVY
210 220 230 240 250
TCQVEHPSLT SPLTVEWRAR SESAQSKMLS GVGGFVLGLL FLGAGLFIYF
260
RNQKGHSGLQ PTGFLS
Length:266
Mass (Da):30,112
Last modified:January 1, 1990 - v1
Checksum:i8116E91DA38294E5
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti154G → A in AAA59805 (PubMed:3476943).Curated1

Polymorphismi

The following alleles of DRB1-4 are known: DRB1*04:01, DRB1*04:02, DRB1*04:03, DRB1*04:04, DRB1*04:05, DRB1*04:06, DRB1*04:07, DRB1*04:08, DRB1*04:09, DRB1*04:10, DRB1*04:11, DRB1*04:12, DRB1*04:13, DRB1*04:14, DRB1*04:15, DRB1*04:16, DRB1*04:17, DRB1*04:18, DRB1*04:19, DRB1*04:20, DRB1*04:21, DRB1*04:22, DRB1*04:23, DRB1*04:24, DRB1*04:25, DRB1*04:26, DRB1*04:27, DRB1*04:28, DRB1*04:29, DRB1*04:30, DRB1*04:31, DRB1*04:32, DRB1*04:33, DRB1*04:34, DRB1*04:35, DRB1*04:36, DRB1*04:37, DRB1*04:38, DRB1*04:39, DRB1*04:40, DRB1*04:41, DRB1*04:42, DRB1*04:43, DRB1*04:44, DRB1*04:45, DRB1*04:46, DRB1*04:47, DRB1*04:48, DRB1*04:49, DRB1*04:50, DRB1*04:51, DRB1*04:52, DRB1*04:53, DRB1*04:54, DRB1*04:55, DRB1*04:56, DRB1*04:57, DRB1*04:58, DRB1*04:59, DRB1*04:60, DRB1*04:61, DRB1*04:62, DRB1*04:63, DRB1*04:64, DRB1*04:65, DRB1*04:66, DRB1*04:67, DRB1*04:68, DRB1*04:69, DRB1*04:70, DRB1*04:71, DRB1*04:72, DRB1*04:73, DRB1*04:74, DRB1*04:75, DRB1*04:76, DRB1*04:77 and DRB1*04:78. The sequence shown is that of DRB1*04:01.

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0565295K → R.Corresponds to variant rs9270305dbSNPEnsembl.1
Natural variantiVAR_01667386D → S in allele DRB1*04:11; requires 2 nucleotide substitutions. 1
Natural variantiVAR_01667496L → I in allele DRB1*04:02. 1
Natural variantiVAR_01667599Q → D in allele DRB1*04:02; requires 2 nucleotide substitutions. 1
Natural variantiVAR_016676100K → E in allele DRB1*04:02. 1
Natural variantiVAR_016677100K → R in allele DRB1*04:03, allele DRB1*04:04 and allele DRB1*04:11. 1
Natural variantiVAR_016678103A → E in allele DRB1*04:03 and allele DRB1*04:11. 1
Natural variantiVAR_016679115G → V in allele DRB1*04:02, allele DRB1*04:03, allele DRB1*04:04 and allele DRB1*04:11. 1
Natural variantiVAR_056530236V → M.Corresponds to variant rs2230816dbSNPEnsembl.1
Natural variantiVAR_056531262T → R.Corresponds to variant rs9269744dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M20548 Genomic DNA. No translation available.
M20549 Genomic DNA. No translation available.
M20550 Genomic DNA. No translation available.
AL137064 Genomic DNA. Translation: CAC19360.1.
M17381 mRNA. Translation: AAA59805.1.
K02776 Genomic DNA. Translation: AAA59808.1.
X96851 Genomic DNA. No translation available.
AJ297586 mRNA. Translation: CAC08826.2.
AF029269 Genomic DNA. Translation: AAF65479.1.
AF112876 Genomic DNA. Translation: AAD29581.1.
AJ295845 Genomic DNA. Translation: CAC08181.1.
X02902 mRNA. Translation: CAA26660.1.
M15069 mRNA. Translation: AAA59809.1.
L42143 mRNA. Translation: AAA67104.1.
PIRiA94681. A29310.
I79419.
UniGeneiHs.534322.
Hs.696211.
Hs.716081.
Hs.723344.
Hs.736560.

Genome annotation databases

EnsembliENST00000419393; ENSP00000403458; ENSG00000228080.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M20548 Genomic DNA. No translation available.
M20549 Genomic DNA. No translation available.
M20550 Genomic DNA. No translation available.
AL137064 Genomic DNA. Translation: CAC19360.1.
M17381 mRNA. Translation: AAA59805.1.
K02776 Genomic DNA. Translation: AAA59808.1.
X96851 Genomic DNA. No translation available.
AJ297586 mRNA. Translation: CAC08826.2.
AF029269 Genomic DNA. Translation: AAF65479.1.
AF112876 Genomic DNA. Translation: AAD29581.1.
AJ295845 Genomic DNA. Translation: CAC08181.1.
X02902 mRNA. Translation: CAA26660.1.
M15069 mRNA. Translation: AAA59809.1.
L42143 mRNA. Translation: AAA67104.1.
PIRiA94681. A29310.
I79419.
UniGeneiHs.534322.
Hs.696211.
Hs.716081.
Hs.723344.
Hs.736560.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1D5MX-ray2.00B30-221[»]
1D5XX-ray2.45B30-221[»]
1D5ZX-ray2.00B30-221[»]
1D6EX-ray2.45B30-221[»]
1J8HX-ray2.40B30-221[»]
2SEBX-ray2.50B30-221[»]
3O6FX-ray2.80B/F31-221[»]
3T0EX-ray4.00B30-221[»]
4IS6X-ray2.50B30-221[»]
4MCYX-ray2.30B30-219[»]
4MCZX-ray2.41B30-219[»]
4MD0X-ray2.19B30-219[»]
4MD4X-ray1.95B30-219[»]
4MD5X-ray1.65B30-219[»]
4MDIX-ray2.00B30-219[»]
4MDJX-ray1.70B30-219[»]
4Y19X-ray2.50B30-219[»]
4Y1AX-ray4.00B30-219[»]
ProteinModelPortaliP13760.
SMRiP13760.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP13760. 6 interactors.

PTM databases

iPTMnetiP13760.
PhosphoSitePlusiP13760.

Polymorphism and mutation databases

DMDMi122253.

Proteomic databases

EPDiP13760.
MaxQBiP13760.
PeptideAtlasiP13760.
PRIDEiP13760.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000419393; ENSP00000403458; ENSG00000228080.

Organism-specific databases

GeneCardsiHLA-DRB1.
H-InvDBHIX0207659.
HGNCiHGNC:4948. HLA-DRB1.
HPAiHPA043151.
MalaCardsiHLA-DRB1.
MIMi142857. gene.
neXtProtiNX_P13760.
GenAtlasiSearch...

Phylogenomic databases

HOVERGENiHBG012730.
PhylomeDBiP13760.

Enzyme and pathway databases

BioCyciZFISH:G66-31956-MONOMER.
ReactomeiR-HSA-202424. Downstream TCR signaling.
R-HSA-202427. Phosphorylation of CD3 and TCR zeta chains.
R-HSA-202430. Translocation of ZAP-70 to Immunological synapse.
R-HSA-202433. Generation of second messenger molecules.
R-HSA-2132295. MHC class II antigen presentation.
R-HSA-389948. PD-1 signaling.
R-HSA-877300. Interferon gamma signaling.

Miscellaneous databases

ChiTaRSiHLA-DRB1. human.
EvolutionaryTraceiP13760.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000228080.
CleanExiHS_HLA-DRB1.

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]
SUPFAMiSSF48726. SSF48726. 1 hit.
SSF54452. SSF54452. 1 hit.
PROSITEiPS50835. IG_LIKE. 1 hit.
PS00290. IG_MHC. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry namei2B14_HUMAN
AccessioniPrimary (citable) accession number: P13760
Secondary accession number(s): O19717
, O19739, P13759, Q29875, Q30145, Q9GIX9, Q9GIY4, Q9MY13, Q9XRY5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 1, 1990
Last sequence update: January 1, 1990
Last modified: November 2, 2016
This is version 161 of the entry and version 1 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

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 one 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.