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Protein

HLA class II histocompatibility antigen, DR beta 4 chain

Gene

HLA-DRB4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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.

Caution

HLA-DRB3, HLA-DRB4 and HLA-DRB5 may represent a unique gene.Curated

GO - Biological processi

Keywordsi

Biological processImmunity

Enzyme and pathway databases

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
SIGNORiP13762

Names & Taxonomyi

Protein namesi
Recommended name:
HLA class II histocompatibility antigen, DR beta 4 chain
Alternative name(s):
MHC class II antigen DRB4
Gene namesi
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

HGNCiHGNC:4952 HLA-DRB4
neXtProtiNX_P13762

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

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

Keywords - Cellular componenti

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

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi254K → R: Almost no change in down-regulation of MHC class II. No ubiquitination and complete loss of down-regulation of MHC class II; when associated with 'R-244' of HLA-DRA. 1 Publication1
Mutagenesisi264L → A: Almost no change in down-regulation of MHC class II; when associated with A-265. 1 Publication1
Mutagenesisi265L → A: Almost no change in down-regulation of MHC class II; when associated with A-264. 1 Publication1

Organism-specific databases

DisGeNETi3126
OpenTargetsiENSG00000227357
PharmGKBiPA35075

Polymorphism and mutation databases

DMDMi281371554

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 29Add BLAST29
ChainiPRO_000001899130 – 266HLA class II histocompatibility antigen, DR beta 4 chainAdd BLAST237

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi44 ↔ 108PROSITE-ProRule annotation
Glycosylationi48N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi146 ↔ 202PROSITE-ProRule annotation
Cross-linki254Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication

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. When associated with ubiquitination of the alpha subunit of HLA-DR: HLA-DRA 'Lys-244', the down-regulation of MHC class II may be highly effective.2 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein, Isopeptide bond, Ubl conjugation

Proteomic databases

PeptideAtlasiP13762
PRIDEiP13762
ProteomicsDBi52984

PTM databases

iPTMnetiP13762

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

BioGridi109371, 10 interactors
IntActiP13762, 1 interactor

Structurei

3D structure databases

ProteinModelPortaliP13762
SMRiP13762
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini126 – 216Ig-like C1-typeAdd BLAST91

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
InParanoidiP13762
KOiK06752
OrthoDBiEOG091G0SXL
PhylomeDBiP13762

Family and domain databases

Gene3Di2.60.40.10, 1 hit
3.10.320.10, 1 hit
InterProiView protein in InterPro
IPR007110 Ig-like_dom
IPR036179 Ig-like_dom_sf
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
PfamiView protein in Pfam
PF07654 C1-set, 1 hit
PF00969 MHC_II_beta, 1 hit
ProDomiView protein in ProDom or Entries sharing at least one domain
PD000328 MHC_II_b_N, 1 hit
SMARTiView protein in SMART
SM00407 IGc1, 1 hit
SM00921 MHC_II_beta, 1 hit
SUPFAMiSSF48726 SSF48726, 1 hit
SSF54452 SSF54452, 1 hit
PROSITEiView protein in PROSITE
PS50835 IG_LIKE, 1 hit
PS00290 IG_MHC, 1 hit

Sequencei

Sequence statusi: Complete.

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

P13762-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MVCLKLPGGS CMAALTVTLT VLSSPLALAG DTQPRFLEQA KCECHFLNGT
60 70 80 90 100
ERVWNLIRYI YNQEEYARYN SDLGEYQAVT ELGRPDAEYW NSQKDLLERR
110 120 130 140 150
RAEVDTYCRY NYGVVESFTV QRRVQPKVTV YPSKTQPLQH HNLLVCSVNG
160 170 180 190 200
FYPGSIEVRW FRNGQEEKAG VVSTGLIQNG DWTFQTLVML ETVPRSGEVY
210 220 230 240 250
TCQVEHPSMM SPLTVQWSAR SESAQSKMLS GVGGFVLGLL FLGTGLFIYF
260
RNQKGHSGLQ PTGLLS
Length:266
Mass (Da):29,941
Last modified:December 15, 2009 - v2
Checksum:i96FF5FE572403FAE
GO

Polymorphismi

The following alleles of DRB4 are known: DRB4*01:01, DRB4*01:02, DRB4*01:03, DRB4*01:04, DRB4*01:05, DRB4*01:06 and DRB4*01:07. The sequence shown is that of DRB4*01:03.

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_060778105D → G in allele DRB4*01:02. 1
Natural variantiVAR_060779106T → N in allele DRB4*01:04. 1
Natural variantiVAR_060780110Y → H in allele DRB4*01:05. 1
Natural variantiVAR_060781113G → R in allele DRB4*01:07. 1
Natural variantiVAR_060782141H → Y in allele DRB4*01:06. 1
Natural variantiVAR_060783164G → S in allele DRB4*01:01 and allele DRB4*01:06. 1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M16942 mRNA Translation: AAA36296.1
AF361548 mRNA Translation: AAM00252.1
AF361549 mRNA Translation: AAM00253.1
DQ284431 mRNA Translation: ABC66198.1
GQ891550 mRNA Translation: ACX50637.1
AK292151 mRNA Translation: BAF84840.1
BX571807 Genomic DNA No translation available.
BX120007 Genomic DNA No translation available.
BX927235 Genomic DNA No translation available.
CR788250 Genomic DNA No translation available.
BC005312 mRNA Translation: AAH05312.1
M15178 mRNA Translation: AAA35995.1
M20555 Genomic DNA Translation: AAA59830.1
AH012539 Genomic DNA Translation: AAO43051.1
AH011268 Genomic DNA Translation: AAL48256.1
AB107960 Genomic DNA Translation: BAC75547.1
Y09313 Genomic DNA Translation: CAA70497.1
AY394720 Genomic DNA Translation: AAQ96922.1
PIRiB28031
I59092
PT0168
RefSeqiNP_068818.4, NM_021983.4
XP_016885779.1, XM_017030290.1
UniGeneiHs.534322
Hs.696211
Hs.716081
Hs.723344

Genome annotation databases

EnsembliENST00000411565; ENSP00000410857; ENSG00000227357
GeneIDi3126
KEGGihsa:3126

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiDRB4_HUMAN
AccessioniPrimary (citable) accession number: P13762
Secondary accession number(s): B0S863
, O78042, P79664, Q29889, Q30163, Q6TLK6, Q860N4, Q861F3, Q8WLT9, Q9BS54
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 1, 1990
Last sequence update: December 15, 2009
Last modified: June 20, 2018
This is version 140 of the entry and version 2 of the sequence. See 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

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. SIMILARITY comments
    Index of protein domains and families

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