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MGP001454

UniProt Annotations

Entry Information
Gene Namemajor histocompatibility complex, class II, DR alpha
Protein EntryDRA_HUMAN
UniProt IDP01903
SpeciesHuman
Comments
Comment typeDescription
FunctionBinds 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.
PolymorphismGenetic variations in HLA-DRA influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].
PolymorphismThe following alleles of DRA are known: DRA*01:01 and DRA*01:02. The sequence shown is that of DRA*01:01.
PtmUbiquitinated by MARCH1 or MARCH8 at Lys-244 leading to down- regulation of MHC class II. When associated with ubiquitination of the beta subunit of HLA-DR: HLA-DRB4 'Lys-254', the down- regulation of MHC class II may be highly effective. {ECO:0000269|PubMed:19117940}.
Sequence CautionSequence=CAA25076.1; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305};
SimilarityBelongs to the MHC class II family. {ECO:0000305}.
SimilarityContains 1 Ig-like C1-type (immunoglobulin-like) domain. {ECO:0000305}.
Subcellular LocationCell membrane; Single-pass type I membrane protein. Endoplasmic reticulum membrane; Single-pass type I membrane protein. Golgi apparatus, trans-Golgi network membrane; Single-pass type I membrane protein. Endosome membrane; Single- pass type I membrane protein. Lysosome membrane; Single-pass type I membrane protein. Late endosome membrane; Single-pass type I membrane protein. 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.
SubunitHeterodimer 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. {ECO:0000269|PubMed:11080454, ECO:0000269|PubMed:11163233, ECO:0000269|PubMed:12244309, ECO:0000269|PubMed:16079912, ECO:0000269|PubMed:17583734, ECO:0000269|PubMed:18697946, ECO:0000269|PubMed:7477400}.
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