UniProt functional annotation for P01903



	UniProt functional annotation for P01903

UniProt code: P01903.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: An alpha chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the beta chain HLA- DRB, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DR-restricted CD4-positive T cells. This guides antigen-specific T- helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:29884618, PubMed:17334368, PubMed:8145819, PubMed:15322540, PubMed:22327072, PubMed:27591323, PubMed:31495665, PubMed:15265931, PubMed:9075930, PubMed:24190431). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self- peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819). {ECO:0000269|PubMed:15265931, ECO:0000269|PubMed:15322540, ECO:0000269|PubMed:17182262, ECO:0000269|PubMed:17334368, ECO:0000269|PubMed:22327072, ECO:0000269|PubMed:23783831, ECO:0000269|PubMed:24190431, ECO:0000269|PubMed:25413013, ECO:0000269|PubMed:27591323, ECO:0000269|PubMed:29884618, ECO:0000269|PubMed:31495665, ECO:0000269|PubMed:8145819, ECO:0000269|PubMed:9075930}.

Subunit: Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB and a peptide (peptide-MHCII) (PubMed:7477400, PubMed:9354468, PubMed:9782128, PubMed:31619516, PubMed:32668259, PubMed:11080454, PubMed:11163233, PubMed:12244309, PubMed:16079912, PubMed:17583734, PubMed:18697946). Newly synthesized alpha and beta chains forms a heterodimer (MHCII) that associates with the CD74/invariant chain (Ii) in the endoplasmic reticulum (ER). Ii is a trimer composed of three subunits and each subunit interacts with one MHCII dimer, blocking the peptide-binding cleft (PubMed:7479981). As a result, MHCII molecules can not bind peptides present in the ER (PubMed:7479981). The complex of MHCII and CD74/Ii is transported in vesicles from ER to Golgi to lysosomes, where it encounters antigenic peptides generated via proteolysis of endocytosed antigens. MHCII dimers are dissociated from CD74/Ii by the combined action of proteolysis and HLA-DM (PubMed:25413013, PubMed:23260142, PubMed:21115828). Lysosomal enzymes such as cathepsin, degrade CD74/Ii leaving a 24 amino acid remnant called class II-associated Ii or CLIP. Interacts (via the peptide binding cleft) with CLIP; this interaction inhibits antigen peptide binding before entry in the endosomal compartment (PubMed:9075930, PubMed:7477400). The displacement of CLIP and replacement by a high affinity peptide in lysosomes is performed by HLA-DM heterodimer. HLA-DM catalyzes CLIP dissociation from MHCII, stabilizes empty MHCII and mediates the selection of high affinity peptides (PubMed:23260142, PubMed:11070170, PubMed:9075930). Interacts with HLA-DM heterodimer; this interaction is direct (PubMed:25413013). Interacts (via alpha-1 domain) with TCR (via CDRs) (PubMed:17334368, PubMed:29884618). Interacts (via alpha-2 domain) with CD4 (via Ig-like V-type domain); this interaction increases the affinity of TCR for peptide-MHCII (PubMed:27114505). {ECO:0000269|PubMed:11070170, ECO:0000269|PubMed:11080454, ECO:0000269|PubMed:11163233, ECO:0000269|PubMed:12244309, ECO:0000269|PubMed:16079912, ECO:0000269|PubMed:17334368, ECO:0000269|PubMed:17583734, ECO:0000269|PubMed:18697946, ECO:0000269|PubMed:21115828, ECO:0000269|PubMed:23260142, ECO:0000269|PubMed:25413013, ECO:0000269|PubMed:27114505, ECO:0000269|PubMed:29884618, ECO:0000269|PubMed:31619516, ECO:0000269|PubMed:32668259, ECO:0000269|PubMed:7477400, ECO:0000269|PubMed:7479981, ECO:0000269|PubMed:9075930, ECO:0000269|PubMed:9354468, ECO:0000269|PubMed:9782128}.

Subunit: (Microbial infection) Interacts with Epstein-Barr virus BZLF2/gp42. {ECO:0000269|PubMed:11864610}.

Subunit: (Microbial infection) Interacts with Staphylococcus aureus enterotoxin A/entA, enterotoxin B/entB, enterotoxin C1/entC1, enterotoxin D/entD, and enterotoxin H/entH. {ECO:0000269|PubMed:11432818, ECO:0000269|PubMed:21081917, ECO:0000269|PubMed:2210803, ECO:0000269|PubMed:2658055, ECO:0000269|PubMed:8152483}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:15322540, ECO:0000269|PubMed:18305173, ECO:0000269|PubMed:29884618}; Single-pass type I membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:18305173}; Single-pass type I membrane protein {ECO:0000255}. Early endosome membrane {ECO:0000269|PubMed:19117940}; Single-pass type I membrane protein {ECO:0000255}. Late endosome membrane {ECO:0000269|PubMed:18305173, ECO:0000269|PubMed:19117940, ECO:0000269|PubMed:9075930}; Single-pass type I membrane protein {ECO:0000255}. Lysosome membrane {ECO:0000269|PubMed:18305173, ECO:0000269|PubMed:9075930}; Single-pass type I membrane protein {ECO:0000255}. Autolysosome membrane {ECO:0000269|PubMed:17182262}; Single-pass type I membrane protein. Note=The MHCII complex transits through a number of intracellular compartments in the endocytic pathway until it reaches the cell membrane for antigen presentation (PubMed:9075930, PubMed:18305173). Component of immunological synapses at the interface between T cell and APC (PubMed:15322540, PubMed:29884618). {ECO:0000269|PubMed:15322540, ECO:0000269|PubMed:18305173, ECO:0000269|PubMed:29884618, ECO:0000269|PubMed:9075930}.

Tissue specificity: Expressed in professional APCs: macrophages, dendritic cells and B cells (at protein level) (PubMed:31495665, PubMed:15322540, PubMed:23783831). Expressed in thymic epithelial cells (at protein level) (PubMed:23783831). {ECO:0000269|PubMed:15322540, ECO:0000269|PubMed:23783831, ECO:0000269|PubMed:31495665}.

Induction: Up-regulated in dendritic cells upon maturation. {ECO:0000269|PubMed:15322540}.

Domain: The alpha-1 domain is a structural part of the peptide-binding cleft. It contains one alpha helix and 4 beta sheets, respectively forming part of the wall and the floor of the peptide-binding cleft. The other 4 beta sheets of the floor and the second alpha helix wall is formed by the beta-1 domain of HLA-DRB. Forms hydrogen bonds with the peptide main chain via conserved amino acids (PubMed:8145819, PubMed:9354468, PubMed:9782128, PubMed:17583734, PubMed:29884618). The peptide-bound alpha-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domain of TCR (PubMed:29884618). {ECO:0000269|PubMed:17583734, ECO:0000269|PubMed:29884618, ECO:0000269|PubMed:8145819, ECO:0000269|PubMed:9354468, ECO:0000269|PubMed:9782128}.

Domain: The alpha-2 Ig-like domain mediates the interaction with CD4 coreceptor. {ECO:0000269|PubMed:27114505}.

Ptm: Ubiquitinated by MARCHF1 or MARCHF8 at Lys-244 leading to down- regulation of MHCII. When associated with ubiquitination of the beta chain at 'Lys-254', the down-regulation of MHCII may be highly effective. {ECO:0000269|PubMed:19117940}.

Polymorphism: The following alleles of DRA are known: DRA*01:01 and DRA*01:02. The sequence shown is that of DRA*01:02.

Similarity: Belongs to the MHC class II family. {ECO:0000305}.

Sequence caution: Sequence=CAA25076.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		An alpha chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the beta chain HLA- DRB, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DR-restricted CD4-positive T cells. This guides antigen-specific T- helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:29884618, PubMed:17334368, PubMed:8145819, PubMed:15322540, PubMed:22327072, PubMed:27591323, PubMed:31495665, PubMed:15265931, PubMed:9075930, PubMed:24190431). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self- peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819). {ECO:0000269\|PubMed:15265931, ECO:0000269\|PubMed:15322540, ECO:0000269\|PubMed:17182262, ECO:0000269\|PubMed:17334368, ECO:0000269\|PubMed:22327072, ECO:0000269\|PubMed:23783831, ECO:0000269\|PubMed:24190431, ECO:0000269\|PubMed:25413013, ECO:0000269\|PubMed:27591323, ECO:0000269\|PubMed:29884618, ECO:0000269\|PubMed:31495665, ECO:0000269\|PubMed:8145819, ECO:0000269\|PubMed:9075930}.


Subunit:		Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB and a peptide (peptide-MHCII) (PubMed:7477400, PubMed:9354468, PubMed:9782128, PubMed:31619516, PubMed:32668259, PubMed:11080454, PubMed:11163233, PubMed:12244309, PubMed:16079912, PubMed:17583734, PubMed:18697946). Newly synthesized alpha and beta chains forms a heterodimer (MHCII) that associates with the CD74/invariant chain (Ii) in the endoplasmic reticulum (ER). Ii is a trimer composed of three subunits and each subunit interacts with one MHCII dimer, blocking the peptide-binding cleft (PubMed:7479981). As a result, MHCII molecules can not bind peptides present in the ER (PubMed:7479981). The complex of MHCII and CD74/Ii is transported in vesicles from ER to Golgi to lysosomes, where it encounters antigenic peptides generated via proteolysis of endocytosed antigens. MHCII dimers are dissociated from CD74/Ii by the combined action of proteolysis and HLA-DM (PubMed:25413013, PubMed:23260142, PubMed:21115828). Lysosomal enzymes such as cathepsin, degrade CD74/Ii leaving a 24 amino acid remnant called class II-associated Ii or CLIP. Interacts (via the peptide binding cleft) with CLIP; this interaction inhibits antigen peptide binding before entry in the endosomal compartment (PubMed:9075930, PubMed:7477400). The displacement of CLIP and replacement by a high affinity peptide in lysosomes is performed by HLA-DM heterodimer. HLA-DM catalyzes CLIP dissociation from MHCII, stabilizes empty MHCII and mediates the selection of high affinity peptides (PubMed:23260142, PubMed:11070170, PubMed:9075930). Interacts with HLA-DM heterodimer; this interaction is direct (PubMed:25413013). Interacts (via alpha-1 domain) with TCR (via CDRs) (PubMed:17334368, PubMed:29884618). Interacts (via alpha-2 domain) with CD4 (via Ig-like V-type domain); this interaction increases the affinity of TCR for peptide-MHCII (PubMed:27114505). {ECO:0000269\|PubMed:11070170, ECO:0000269\|PubMed:11080454, ECO:0000269\|PubMed:11163233, ECO:0000269\|PubMed:12244309, ECO:0000269\|PubMed:16079912, ECO:0000269\|PubMed:17334368, ECO:0000269\|PubMed:17583734, ECO:0000269\|PubMed:18697946, ECO:0000269\|PubMed:21115828, ECO:0000269\|PubMed:23260142, ECO:0000269\|PubMed:25413013, ECO:0000269\|PubMed:27114505, ECO:0000269\|PubMed:29884618, ECO:0000269\|PubMed:31619516, ECO:0000269\|PubMed:32668259, ECO:0000269\|PubMed:7477400, ECO:0000269\|PubMed:7479981, ECO:0000269\|PubMed:9075930, ECO:0000269\|PubMed:9354468, ECO:0000269\|PubMed:9782128}.
Subunit:		(Microbial infection) Interacts with Epstein-Barr virus BZLF2/gp42. {ECO:0000269\|PubMed:11864610}.
Subunit:		(Microbial infection) Interacts with Staphylococcus aureus enterotoxin A/entA, enterotoxin B/entB, enterotoxin C1/entC1, enterotoxin D/entD, and enterotoxin H/entH. {ECO:0000269\|PubMed:11432818, ECO:0000269\|PubMed:21081917, ECO:0000269\|PubMed:2210803, ECO:0000269\|PubMed:2658055, ECO:0000269\|PubMed:8152483}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:15322540, ECO:0000269\|PubMed:18305173, ECO:0000269\|PubMed:29884618}; Single-pass type I membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000269\|PubMed:18305173}; Single-pass type I membrane protein {ECO:0000255}. Early endosome membrane {ECO:0000269\|PubMed:19117940}; Single-pass type I membrane protein {ECO:0000255}. Late endosome membrane {ECO:0000269\|PubMed:18305173, ECO:0000269\|PubMed:19117940, ECO:0000269\|PubMed:9075930}; Single-pass type I membrane protein {ECO:0000255}. Lysosome membrane {ECO:0000269\|PubMed:18305173, ECO:0000269\|PubMed:9075930}; Single-pass type I membrane protein {ECO:0000255}. Autolysosome membrane {ECO:0000269\|PubMed:17182262}; Single-pass type I membrane protein. Note=The MHCII complex transits through a number of intracellular compartments in the endocytic pathway until it reaches the cell membrane for antigen presentation (PubMed:9075930, PubMed:18305173). Component of immunological synapses at the interface between T cell and APC (PubMed:15322540, PubMed:29884618). {ECO:0000269\|PubMed:15322540, ECO:0000269\|PubMed:18305173, ECO:0000269\|PubMed:29884618, ECO:0000269\|PubMed:9075930}.
Tissue specificity:		Expressed in professional APCs: macrophages, dendritic cells and B cells (at protein level) (PubMed:31495665, PubMed:15322540, PubMed:23783831). Expressed in thymic epithelial cells (at protein level) (PubMed:23783831). {ECO:0000269\|PubMed:15322540, ECO:0000269\|PubMed:23783831, ECO:0000269\|PubMed:31495665}.
Induction:		Up-regulated in dendritic cells upon maturation. {ECO:0000269\|PubMed:15322540}.
Domain:		The alpha-1 domain is a structural part of the peptide-binding cleft. It contains one alpha helix and 4 beta sheets, respectively forming part of the wall and the floor of the peptide-binding cleft. The other 4 beta sheets of the floor and the second alpha helix wall is formed by the beta-1 domain of HLA-DRB. Forms hydrogen bonds with the peptide main chain via conserved amino acids (PubMed:8145819, PubMed:9354468, PubMed:9782128, PubMed:17583734, PubMed:29884618). The peptide-bound alpha-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domain of TCR (PubMed:29884618). {ECO:0000269\|PubMed:17583734, ECO:0000269\|PubMed:29884618, ECO:0000269\|PubMed:8145819, ECO:0000269\|PubMed:9354468, ECO:0000269\|PubMed:9782128}.
Domain:		The alpha-2 Ig-like domain mediates the interaction with CD4 coreceptor. {ECO:0000269\|PubMed:27114505}.
Ptm:		Ubiquitinated by MARCHF1 or MARCHF8 at Lys-244 leading to down- regulation of MHCII. When associated with ubiquitination of the beta chain at 'Lys-254', the down-regulation of MHCII may be highly effective. {ECO:0000269\|PubMed:19117940}.
Polymorphism:		The following alleles of DRA are known: DRA01:01 and DRA01:02. The sequence shown is that of DRA*01:02.
Similarity:		Belongs to the MHC class II family. {ECO:0000305}.
Sequence caution:		Sequence=CAA25076.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};