UniProt functional annotation for P10321



	UniProt functional annotation for P10321

UniProt code: P10321.

Organism: Homo sapiens (Human).

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

Function: Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity (PubMed:20972337, PubMed:24091323, PubMed:20439706, PubMed:11172028, PubMed:20104487, PubMed:28649982, PubMed:29312307). In complex with B2M/beta 2 microglobulin displays a restricted repertoire of self and viral peptides and acts as a dominant ligand for inhibitory and activating killer immunoglobulin receptors (KIRs) expressed on NK cells (PubMed:16141329). In an allogeneic setting, such as during pregnancy, mediates interaction of extravillous trophoblasts with KIR on uterine NK cells and regulate trophoblast invasion necessary for placentation and overall fetal growth (PubMed:20972337, PubMed:24091323). During viral infection, may present viral peptides with low affinity for KIRs, impeding KIR-mediated inhibition through peptide antagonism and favoring lysis of infected cells (PubMed:20439706). Presents a restricted repertoire of viral peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-C-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected cells, particularly in chronic viral infection settings such as HIV-1 or CMV infection (PubMed:11172028, PubMed:20104487, PubMed:28649982). Both the peptide and the MHC molecule are recognized by TCR, the peptide is responsible for the fine specificity of antigen recognition and MHC residues account for the MHC restriction of T cells (By similarity). Typically presents intracellular peptide antigens of 9 amino acids that arise from cytosolic proteolysis via proteasome. Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9. Preferentially displays peptides having a restricted repertoire of hydrophobic or aromatic amino acids (Phe, Ile, Leu, Met, Val and Tyr) at the C-terminal anchor (PubMed:8265661, PubMed:25311805). {ECO:0000250|UniProtKB:P04439, ECO:0000269|PubMed:11172028, ECO:0000269|PubMed:16141329, ECO:0000269|PubMed:20104487, ECO:0000269|PubMed:20439706, ECO:0000269|PubMed:20972337, ECO:0000269|PubMed:24091323, ECO:0000269|PubMed:25311805, ECO:0000269|PubMed:28649982, ECO:0000269|PubMed:29312307, ECO:0000269|PubMed:8265661}.

Function: ALLELE C*01:02: The peptide-bound form interacts with KIR2DL2 and KIR2DL3 inhibitory receptors on NK cells. The low affinity peptides compete with the high affinity peptides impeding KIR-mediated inhibition and favoring lysis of infected cells (PubMed:20439706). Presents to CD8-positive T cells a CMV epitope derived from UL83/pp65 (RCPEMISVL), an immediate-early antigen necessary for initiating viral replication (PubMed:12947002). {ECO:0000269|PubMed:12947002, ECO:0000269|PubMed:20439706}.

Function: ALLELE C*04:01: Presents a conserved HIV-1 epitope derived from env (SFNCGGEFF) to memory CD8-positive T cells, eliciting very strong IFNG responses (PubMed:20104487). Presents CMV epitope derived from UL83/pp65 (QYDPVAALF) to CD8-positive T cells, triggering T cell cytotoxic response (PubMed:12947002). {ECO:0000269|PubMed:12947002, ECO:0000269|PubMed:20104487}.

Function: ALLELE C*05:01: Presents HIV-1 epitope derived from rev (SAEPVPLQL) to CD8-positive T cells, triggering T cell cytotoxic response. {ECO:0000269|PubMed:11172028}.

Function: ALLELE C*06:02: In trophoblasts, interacts with KIR2DS2 on uterine NK cells and triggers NK cell activation, including secretion of cytokines such as GMCSF that enhances trophoblast migration. {ECO:0000269|PubMed:24091323}.

Function: ALLELE C*07:02: Plays an important role in the control of chronic CMV infection. Presents immunodominant CMV epitopes derived from IE1 (LSEFCRVL and CRVLCCYVL) and UL28 (FRCPRRFCF), both antigens synthesized during immediate-early period of viral replication. Elicits a strong anti-viral CD8-positive T cell immune response that increases markedly with age. {ECO:0000269|PubMed:29312307}.

Function: ALLELE C*08:01: Presents viral epitopes derived from CMV UL83 (VVCAHELVC) and IAV M1 (GILGFVFTL), triggering CD8-positive T cell cytotoxic response. {ECO:0000269|PubMed:12947002, ECO:0000269|PubMed:24990997}.

Function: ALLELE C*12:02: Presents CMV epitope derived from UL83 (VAFTSHEHF) to CD8-positive T cells. {ECO:0000269|PubMed:12947002}.

Function: ALLELE C*15:02: Presents CMV epitope derived from UL83 CC (VVCAHELVC) to CD8-positive T cells, triggering T cell cytotoxic response. {ECO:0000269|PubMed:12947002}.

Subunit: Heterotrimer that consists of an alpha chain HLA-C, a beta chain B2M and a peptide (peptide-HLA-C-B2M) (PubMed:28649982, PubMed:10850706, PubMed:24990997). Early in biogenesis, HLA-C-B2M dimer interacts with the components of the peptide-loading complex composed of TAPBP, TAP1-TAP2, TAPBPL, PDIA3/ERP57 and CALR (PubMed:18420581). Interacts with TAP1-TAP2 transporter via TAPBP; this interaction is obligatory for the loading of peptide epitopes delivered to the endoplasmic reticulum (ER) by TAP1-TAP2 transporter (By similarity). Being very selective in the peptide binding, forms a stable interaction with TAP1-TAP2, often leading to the accumulation of free heavy chains in the ER (PubMed:18420581). Only optimally assembled peptide-HLA-C-B2M trimer translocates to the surface of antigen-presenting cells, where it interacts with TCR and CD8 coreceptor on the surface of T cells. HLA-C (via polymorphic alpha-1 and alpha-2 domains) interacts with antigen-specific TCR (via CDR3 domains) (By similarity). One HLA-C molecule (mainly via nonpolymorphic alpha-3 domain) interacts with one CD8A homodimer (via CDR-like loop); this interaction insures peptide- HLA-C-B2M recognition by CD8-positive T cells only (By similarity). The peptide-HLA-C-B2M complex also interacts with KIRs. HLA-C type 1 (C1, with Asn104), including HLA-C*02, C*04, C*05, C*06 and C*15, interact with KIR2DL1 and KIR2DS1, and HLA-C type 2 (C2, with Lys104), including HLA-C*01, C*03, C*07 and C*08, interact with KIR2DL2 and KIR2DL3 (PubMed:20972337, PubMed:24091323, PubMed:16141329, PubMed:20439706, PubMed:11323700, PubMed:10850706). {ECO:0000250|UniProtKB:P04439, ECO:0000269|PubMed:10850706, ECO:0000269|PubMed:11323700, ECO:0000269|PubMed:16141329, ECO:0000269|PubMed:18420581, ECO:0000269|PubMed:20439706, ECO:0000269|PubMed:20972337, ECO:0000269|PubMed:24091323, ECO:0000269|PubMed:24990997, ECO:0000269|PubMed:28649982}.

Subunit: (Microbial infection) Interacts with HTLV-1 p12I accessory protein. {ECO:0000269|PubMed:11390610}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:18420581, ECO:0000269|PubMed:20972337, ECO:0000269|PubMed:28649982}; Single-pass type I membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000305|PubMed:18420581}; Single-pass membrane protein {ECO:0000255}.

Tissue specificity: Ubiquitous. Highly expressed in fetal extravillous trophoblasts in the decidua basalis (at protein level). {ECO:0000269|PubMed:20972337}.

Domain: The alpha-1 domain is a structural part of the peptide-binding cleft. {ECO:0000269|PubMed:28649982}.

Domain: The alpha-2 domain is a structural part of the peptide-binding cleft (PubMed:28649982, PubMed:10850706, PubMed:24990997). Mediates the interaction with TAP1-TAP2 complex. {ECO:0000269|PubMed:10850706, ECO:0000269|PubMed:24990997, ECO:0000269|PubMed:28649982}.

Domain: The alpha-3 Ig-like domain mediates the interaction with CD8 coreceptor. {ECO:0000250|UniProtKB:P04439}.

Ptm: N-linked glycosylation at Asn-110 is required for efficient interaction with CANX and CALR chaperones and appropriate HLA-C-B2M folded conformers prior to peptide loading. {ECO:0000269|PubMed:18420581, ECO:0000269|PubMed:19159218}.

Polymorphism: Displays lower polymorphism than HLA-A and HLA-B. Polymorphic residues encode for alpha-1 and alpha-2 domains of the peptide-binding cleft, where they contribute to variations in peptide binding and TCR recognition among different alleles. The human population is estimated to have millions of HLA-C alleles. But only 14 common HLA-C alleles are considered core alleles, representing all functionally significant variation (polymorphism) in alpha-1 and alpha- 2 domains. These are: C*01:02; C*02:02; C*03:02; C*04:01; C*05:01; C*06:02; C*07:01; C*07:04; C*08:01; C*12:02; C*14:02; C*15:02; C*16:01 and C*17:01. Among these, C*01:02; C*02:02; C*03:02; C*08:01; C*12:02; C*14:02 and C*15:02, were likely passed by introgression from archaic to modern humans. Functional alleles of more recent origin (non-core) were derived by recombination (PubMed:28650991). The sequence shown is that of C*07:02. The sequences of core alleles and common representative alleles of serologically distinct allele groups are described as variants of C*07:02. {ECO:0000269|PubMed:28650991, ECO:0000305}.

Disease: Psoriasis 1 (PSORS1) [MIM:177900]: A common, chronic inflammatory disease of the skin with multifactorial etiology. It is characterized by red, scaly plaques usually found on the scalp, elbows and knees. These lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis. {ECO:0000269|PubMed:16642438}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. Allele C*06:02 presents a melanocyte autoantigen ADAMTSL5 (VRSRRCLRL) to Valpha3S1/Vbeta13S1 TCR on CD8- positive T cells, and may trigger an autoimmune response against melanocytes. {ECO:0000269|PubMed:26621454}.

Miscellaneous: [Isoform 2]: A transcript of allele C*16:01. This isoform lacks the transmembrane domain and is predicted to be a secreted protein. {ECO:0000305|PubMed:2914713}.

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:		Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity (PubMed:20972337, PubMed:24091323, PubMed:20439706, PubMed:11172028, PubMed:20104487, PubMed:28649982, PubMed:29312307). In complex with B2M/beta 2 microglobulin displays a restricted repertoire of self and viral peptides and acts as a dominant ligand for inhibitory and activating killer immunoglobulin receptors (KIRs) expressed on NK cells (PubMed:16141329). In an allogeneic setting, such as during pregnancy, mediates interaction of extravillous trophoblasts with KIR on uterine NK cells and regulate trophoblast invasion necessary for placentation and overall fetal growth (PubMed:20972337, PubMed:24091323). During viral infection, may present viral peptides with low affinity for KIRs, impeding KIR-mediated inhibition through peptide antagonism and favoring lysis of infected cells (PubMed:20439706). Presents a restricted repertoire of viral peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-C-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected cells, particularly in chronic viral infection settings such as HIV-1 or CMV infection (PubMed:11172028, PubMed:20104487, PubMed:28649982). Both the peptide and the MHC molecule are recognized by TCR, the peptide is responsible for the fine specificity of antigen recognition and MHC residues account for the MHC restriction of T cells (By similarity). Typically presents intracellular peptide antigens of 9 amino acids that arise from cytosolic proteolysis via proteasome. Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9. Preferentially displays peptides having a restricted repertoire of hydrophobic or aromatic amino acids (Phe, Ile, Leu, Met, Val and Tyr) at the C-terminal anchor (PubMed:8265661, PubMed:25311805). {ECO:0000250\|UniProtKB:P04439, ECO:0000269\|PubMed:11172028, ECO:0000269\|PubMed:16141329, ECO:0000269\|PubMed:20104487, ECO:0000269\|PubMed:20439706, ECO:0000269\|PubMed:20972337, ECO:0000269\|PubMed:24091323, ECO:0000269\|PubMed:25311805, ECO:0000269\|PubMed:28649982, ECO:0000269\|PubMed:29312307, ECO:0000269\|PubMed:8265661}.



Function:		ALLELE C*01:02: The peptide-bound form interacts with KIR2DL2 and KIR2DL3 inhibitory receptors on NK cells. The low affinity peptides compete with the high affinity peptides impeding KIR-mediated inhibition and favoring lysis of infected cells (PubMed:20439706). Presents to CD8-positive T cells a CMV epitope derived from UL83/pp65 (RCPEMISVL), an immediate-early antigen necessary for initiating viral replication (PubMed:12947002). {ECO:0000269\|PubMed:12947002, ECO:0000269\|PubMed:20439706}.



Function:		ALLELE C*04:01: Presents a conserved HIV-1 epitope derived from env (SFNCGGEFF) to memory CD8-positive T cells, eliciting very strong IFNG responses (PubMed:20104487). Presents CMV epitope derived from UL83/pp65 (QYDPVAALF) to CD8-positive T cells, triggering T cell cytotoxic response (PubMed:12947002). {ECO:0000269\|PubMed:12947002, ECO:0000269\|PubMed:20104487}.



Function:		ALLELE C*05:01: Presents HIV-1 epitope derived from rev (SAEPVPLQL) to CD8-positive T cells, triggering T cell cytotoxic response. {ECO:0000269\|PubMed:11172028}.



Function:		ALLELE C*06:02: In trophoblasts, interacts with KIR2DS2 on uterine NK cells and triggers NK cell activation, including secretion of cytokines such as GMCSF that enhances trophoblast migration. {ECO:0000269\|PubMed:24091323}.



Function:		ALLELE C*07:02: Plays an important role in the control of chronic CMV infection. Presents immunodominant CMV epitopes derived from IE1 (LSEFCRVL and CRVLCCYVL) and UL28 (FRCPRRFCF), both antigens synthesized during immediate-early period of viral replication. Elicits a strong anti-viral CD8-positive T cell immune response that increases markedly with age. {ECO:0000269\|PubMed:29312307}.



Function:		ALLELE C*08:01: Presents viral epitopes derived from CMV UL83 (VVCAHELVC) and IAV M1 (GILGFVFTL), triggering CD8-positive T cell cytotoxic response. {ECO:0000269\|PubMed:12947002, ECO:0000269\|PubMed:24990997}.



Function:		ALLELE C*12:02: Presents CMV epitope derived from UL83 (VAFTSHEHF) to CD8-positive T cells. {ECO:0000269\|PubMed:12947002}.



Function:		ALLELE C*15:02: Presents CMV epitope derived from UL83 CC (VVCAHELVC) to CD8-positive T cells, triggering T cell cytotoxic response. {ECO:0000269\|PubMed:12947002}.


Subunit:		Heterotrimer that consists of an alpha chain HLA-C, a beta chain B2M and a peptide (peptide-HLA-C-B2M) (PubMed:28649982, PubMed:10850706, PubMed:24990997). Early in biogenesis, HLA-C-B2M dimer interacts with the components of the peptide-loading complex composed of TAPBP, TAP1-TAP2, TAPBPL, PDIA3/ERP57 and CALR (PubMed:18420581). Interacts with TAP1-TAP2 transporter via TAPBP; this interaction is obligatory for the loading of peptide epitopes delivered to the endoplasmic reticulum (ER) by TAP1-TAP2 transporter (By similarity). Being very selective in the peptide binding, forms a stable interaction with TAP1-TAP2, often leading to the accumulation of free heavy chains in the ER (PubMed:18420581). Only optimally assembled peptide-HLA-C-B2M trimer translocates to the surface of antigen-presenting cells, where it interacts with TCR and CD8 coreceptor on the surface of T cells. HLA-C (via polymorphic alpha-1 and alpha-2 domains) interacts with antigen-specific TCR (via CDR3 domains) (By similarity). One HLA-C molecule (mainly via nonpolymorphic alpha-3 domain) interacts with one CD8A homodimer (via CDR-like loop); this interaction insures peptide- HLA-C-B2M recognition by CD8-positive T cells only (By similarity). The peptide-HLA-C-B2M complex also interacts with KIRs. HLA-C type 1 (C1, with Asn104), including HLA-C02, C04, C05, C06 and C15, interact with KIR2DL1 and KIR2DS1, and HLA-C type 2 (C2, with Lys104), including HLA-C01, C03, C07 and C*08, interact with KIR2DL2 and KIR2DL3 (PubMed:20972337, PubMed:24091323, PubMed:16141329, PubMed:20439706, PubMed:11323700, PubMed:10850706). {ECO:0000250\|UniProtKB:P04439, ECO:0000269\|PubMed:10850706, ECO:0000269\|PubMed:11323700, ECO:0000269\|PubMed:16141329, ECO:0000269\|PubMed:18420581, ECO:0000269\|PubMed:20439706, ECO:0000269\|PubMed:20972337, ECO:0000269\|PubMed:24091323, ECO:0000269\|PubMed:24990997, ECO:0000269\|PubMed:28649982}.
Subunit:		(Microbial infection) Interacts with HTLV-1 p12I accessory protein. {ECO:0000269\|PubMed:11390610}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:18420581, ECO:0000269\|PubMed:20972337, ECO:0000269\|PubMed:28649982}; Single-pass type I membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000305\|PubMed:18420581}; Single-pass membrane protein {ECO:0000255}.
Tissue specificity:		Ubiquitous. Highly expressed in fetal extravillous trophoblasts in the decidua basalis (at protein level). {ECO:0000269\|PubMed:20972337}.
Domain:		The alpha-1 domain is a structural part of the peptide-binding cleft. {ECO:0000269\|PubMed:28649982}.
Domain:		The alpha-2 domain is a structural part of the peptide-binding cleft (PubMed:28649982, PubMed:10850706, PubMed:24990997). Mediates the interaction with TAP1-TAP2 complex. {ECO:0000269\|PubMed:10850706, ECO:0000269\|PubMed:24990997, ECO:0000269\|PubMed:28649982}.
Domain:		The alpha-3 Ig-like domain mediates the interaction with CD8 coreceptor. {ECO:0000250\|UniProtKB:P04439}.
Ptm:		N-linked glycosylation at Asn-110 is required for efficient interaction with CANX and CALR chaperones and appropriate HLA-C-B2M folded conformers prior to peptide loading. {ECO:0000269\|PubMed:18420581, ECO:0000269\|PubMed:19159218}.
Polymorphism:		Displays lower polymorphism than HLA-A and HLA-B. Polymorphic residues encode for alpha-1 and alpha-2 domains of the peptide-binding cleft, where they contribute to variations in peptide binding and TCR recognition among different alleles. The human population is estimated to have millions of HLA-C alleles. But only 14 common HLA-C alleles are considered core alleles, representing all functionally significant variation (polymorphism) in alpha-1 and alpha- 2 domains. These are: C01:02; C02:02; C03:02; C04:01; C05:01; C06:02; C07:01; C07:04; C08:01; C12:02; C14:02; C15:02; C16:01 and C17:01. Among these, C01:02; C02:02; C03:02; C08:01; C12:02; C14:02 and C15:02, were likely passed by introgression from archaic to modern humans. Functional alleles of more recent origin (non-core) were derived by recombination (PubMed:28650991). The sequence shown is that of C07:02. The sequences of core alleles and common representative alleles of serologically distinct allele groups are described as variants of C*07:02. {ECO:0000269\|PubMed:28650991, ECO:0000305}.
Disease:		Psoriasis 1 (PSORS1) [MIM:177900]: A common, chronic inflammatory disease of the skin with multifactorial etiology. It is characterized by red, scaly plaques usually found on the scalp, elbows and knees. These lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis. {ECO:0000269\|PubMed:16642438}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. Allele C*06:02 presents a melanocyte autoantigen ADAMTSL5 (VRSRRCLRL) to Valpha3S1/Vbeta13S1 TCR on CD8- positive T cells, and may trigger an autoimmune response against melanocytes. {ECO:0000269\|PubMed:26621454}.
Miscellaneous:		[Isoform 2]: A transcript of allele C*16:01. This isoform lacks the transmembrane domain and is predicted to be a secreted protein. {ECO:0000305\|PubMed:2914713}.