Affinage

HLA-C

HLA class I histocompatibility antigen, C alpha chain · UniProt P10321

Round 2 corrected
Length
366 aa
Mass
40.6 kDa
Annotated
2026-04-28
130 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HLA-C is a classical MHC class I glycoprotein that presents intracellular peptides to CD8+ cytotoxic T lymphocytes and serves as the principal ligand for KIR2D-family receptors on NK cells, with a C1/C2 epitope dimorphism at positions 77/80 determining KIR specificity and governing NK cell inhibition or activation (PMID:8265660, PMID:7650491, PMID:33846289). Assembly in the ER proceeds through the calreticulin–tapasin–TAP peptide-loading complex, but a locus-specific KYRV motif at residues 66–76 creates a biosynthetic bottleneck that renders HLA-C peptide-selective and contributes to its characteristically low surface expression; ERAP1-mediated peptide trimming is specifically required for efficient HLA-C surface presentation, with an ERAP1 psoriasis-risk haplotype enhancing generation of the HLA-C*06:02-restricted ADAMTSL5 autoantigen (PMID:17956861, PMID:34580106, PMID:8769474). Cell-surface HLA-C expression is regulated transcriptionally by an NK cell-specific promoter with an Ets-binding polymorphism and post-transcriptionally by miR-148a targeting the 3′ UTR, and is selectively downregulated during HIV-1 infection by Vpu (but not Nef) through transmembrane domain interactions that impair HLA-C-restricted CTL responses (PMID:29329284, PMID:21907013, PMID:30180214). HLA-C is also expressed on extravillous trophoblast where it regulates uterine NK cell activity, and associates with HIV-1 gp120/Env as β2m-free chains on infected cells to enhance viral infectivity (PMID:10833373, PMID:18673537, PMID:28051183).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1977 High

    Establishing that HLA-C is a distinct ~43 kDa glycoprotein associated with β2-microglobulin resolved its structural identity as a bona fide MHC class I molecule expressed at lower surface levels than HLA-A/B.

    Evidence Biochemical fractionation, lectin-Sepharose, and sedimentation analysis of HLA-CW2

    PMID:332508

    Open questions at the time
    • No peptide-binding characterization
    • Mechanism of low surface expression unknown
  2. 1988 High

    Demonstrating that HLA-Cw3 functioned as a transplantation antigen and CTL restriction element in transgenic mice established that HLA-C is not a pseudogene but has immunological function comparable to HLA-A/B.

    Evidence HLA-Cw3 transgenic mice, skin graft rejection, virus-specific CTL assays

    PMID:2840670

    Open questions at the time
    • NK cell ligand role not yet recognized
    • No endogenous peptide repertoire defined
  3. 1993 High

    Identifying HLA-C alleles as the dominant inhibitory ligands for NK cells, with C1 versus C2 group specificity defined by residues 77/80, established the central role of HLA-C in innate immune surveillance.

    Evidence HLA-C allele transfection into class I-deleted cell lines, NK cytotoxicity assays

    PMID:8265660

    Open questions at the time
    • Receptor identity (KIR) not yet molecularly defined at this point
    • Structural basis of C1/C2 recognition unknown
  4. 1995 High

    Resolving that HLA-C-recognizing p58 receptors exist as biochemically distinct inhibitory (~58 kDa) and activating (~50 kDa) isoforms explained how a single ligand system can generate opposing NK cell signals.

    Evidence Receptor cross-linking, Ca²⁺ flux, deglycosylation and peptide mapping, NK cytotoxicity with HLA-Cw4 transfectants

    PMID:7650491

    Open questions at the time
    • Structural basis of activating versus inhibitory signaling not defined
    • Full KIR allelic diversity not yet explored
  5. 1996 High

    Characterizing the calreticulin–tapasin–TAP peptide-loading complex as essential for MHC class I assembly provided the ER chaperone framework within which HLA-C-specific assembly bottlenecks would later be understood.

    Evidence Co-immunoprecipitation in tapasin-deficient .220 mutant cells

    PMID:8769474

    Open questions at the time
    • HLA-C-specific assembly behavior not distinguished from HLA-A/B at this point
  6. 1997 High

    Measuring KIR–HLA-C binding kinetics by SPR revealed unusually fast on/off rates, and showing peptide-dependence of KIR–HLA-C recognition established that the bound peptide contributes to the interaction interface.

    Evidence Surface plasmon resonance with recombinant soluble KIR and HLA-C proteins; native gel shift with domain-deletion mutants

    PMID:9378975 PMID:9768753

    Open questions at the time
    • Atomic-level structural details of the KIR–HLA-C interface unresolved
    • Range of peptides modulating binding not systematically explored
  7. 2000 High

    Detecting HLA-C protein on extravillous trophoblast with biallelic expression and IFN-γ responsiveness established HLA-C as a key MHC molecule at the maternal–fetal interface, distinct from HLA-G in its regulation.

    Evidence Flow cytometric sorting of first-trimester trophoblast, cDNA sequencing, IFN-γ treatment

    PMID:10833373

    Open questions at the time
    • Functional consequences for uterine NK cell tolerance not directly tested
    • Relative importance of HLA-C versus HLA-G for pregnancy outcome unknown
  8. 2000 High

    Mapping two clusters of polymorphic residues on KIR2D that determine C1 versus C2 group specificity provided the first molecular basis for allotype-specific NK cell inhibition patterns.

    Evidence Site-directed mutagenesis of KIR chimeric proteins with CD3-ζ signaling assays

    PMID:10820396

    Open questions at the time
    • Crystal structures of KIR–HLA-C complexes not yet available
  9. 2002 High

    Demonstrating direct interaction between CD160 and HLA-C broadened the receptor repertoire for HLA-C beyond KIR family members and showed CD160 engagement triggers NK cytotoxicity.

    Evidence Anti-CD160 blocking antibody, recombinant soluble HLA-Cw3/CD160 binding assay

    PMID:12486241

    Open questions at the time
    • Physiological relevance relative to KIR not established
    • Binding affinity not quantified
  10. 2007 High

    Identifying the KYRV motif as causing a locus-specific biosynthetic bottleneck explained why HLA-C is retained intracellularly as both β2m-associated and free forms and is peptide-selective rather than peptide-unreceptive.

    Evidence Pulse-chase, co-IP with TAP/tapasin, molecular dynamics, in vitro assembly in T2 and 721.220 extracts

    PMID:17956861

    Open questions at the time
    • Whether the KYRV bottleneck specifically selects peptide repertoires important for KIR recognition was untested
    • Structural basis of KYRV effect on groove plasticity not crystallographically confirmed
  11. 2008 High

    Showing that HIV-1 gp120 associates with HLA-C on infected cells and that virion-incorporated HLA-C enhances infectivity revealed an unexpected viral exploitation of this molecule.

    Evidence siRNA knockdown, syncytia formation, pseudovirus infectivity, co-purification from fusion complexes

    PMID:18673537

    Open questions at the time
    • Whether the HLA-C/gp120 interaction is direct or bridged by other factors unclear
    • Relevance to in vivo transmission not tested
  12. 2008 High

    Synergistic polymorphism at positions distal to the ligand-binding site (Pro16Arg in D1 and Arg148Cys in D2) explained the stronger HLA-C binding of KIR2DL2 relative to KIR2DL3 by altering the interdomain hinge angle.

    Evidence Mutagenesis of recombinant KIR, binding panel across 93 HLA isoforms

    PMID:18322206

    Open questions at the time
    • Structural confirmation of hinge angle change awaited crystal structures
  13. 2011 Medium

    Identifying miR-148a targeting of the HLA-C 3′ UTR as a determinant of allotype-specific surface expression, with evolutionary escape via HLA-B sequence exchange ~3–5 Mya, established post-transcriptional regulation as a major axis of HLA-C expression variation.

    Evidence Molecular evolutionary analysis, miRNA binding site characterization

    PMID:21907013

    Open questions at the time
    • Functional validation of miR-148a effect on protein levels in primary cells limited
    • Contribution of miR-148a relative to promoter-level regulation not quantified
  14. 2016 High

    Demonstrating that HIV-1 Vpu—not Nef—selectively downregulates HLA-C via transmembrane domain contacts, reducing HLA-C-restricted CTL responses, resolved the specific viral immune evasion mechanism targeting this locus.

    Evidence Primary HIV-1 isolate panel, Vpu mutant viruses, CTL suppression assays in CD4+ cells

    PMID:27173934

    Open questions at the time
    • Molecular mechanism of Vpu-mediated HLA-C degradation (proteasomal vs. lysosomal) not resolved
  15. 2017 Medium

    Showing that HIV-1 Env specifically associates with β2m-free HLA-C chains—requiring prior correct assembly—clarified the conformational state of HLA-C exploited by HIV for enhanced infectivity.

    Evidence β2m-free HLA-C chain detection, β2m knockout, pseudovirus infectivity assays

    PMID:28051183

    Open questions at the time
    • Direct binding interface between Env and HLA-C free chains not structurally resolved
    • Single-study finding
  16. 2018 High

    Mapping an NK cell-specific HLA-C promoter with Ets-binding site polymorphisms and maturation-dependent alternative splicing revealed a dedicated transcriptional program controlling HLA-C expression in NK cells.

    Evidence Promoter reporter assays, transcript/splicing analysis, NK maturation tracking, flow cytometry

    PMID:29329284

    Open questions at the time
    • Transcription factors binding the NK-specific promoter not fully identified
    • Interplay between NK promoter and miR-148a regulation unexplored
  17. 2018 High

    Identifying 5 Vpu and 4 HLA-C transmembrane residues governing their interaction, and showing that Vpu-mediated downregulation adapts to host HLA-C genotype, defined the co-evolutionary interface between virus and host.

    Evidence 128 replication-competent primary viral isolates, Vpu from 195 treatment-naïve individuals, transmembrane mutagenesis

    PMID:30180214

    Open questions at the time
    • Whether Vpu targets HLA-C to ER-associated degradation or endolysosomal pathway unresolved
  18. 2021 High

    Crystal structures of KIR2DL2 and KIR2DL3 with HLA-C*07:02 revealed distinct docking geometries over the same ligand, providing the atomic-level explanation for differential NK cell inhibition by C1 allotypes.

    Evidence X-ray crystallography, site-directed mutagenesis, primary NK cell inhibition assays

    PMID:33846289

    Open questions at the time
    • Structures with C2-group HLA-C allotypes not yet available
    • Dynamic aspects of the interaction not captured
  19. 2021 High

    Demonstrating that ERAP1 specifically trims N-extended precursors to generate the HLA-C*06:02-restricted ADAMTSL5 autoantigen in psoriasis, with risk haplotype-dependent efficiency, established a direct mechanistic link between peptide processing and autoimmune disease.

    Evidence ERAP1 risk/protective haplotype cell lines, ERAP1 knockout, autoreactive TCR activation assay

    PMID:34580106

    Open questions at the time
    • Full peptide repertoire presented by HLA-C*06:02 under different ERAP1 haplotypes not catalogued
    • In vivo validation in patient-derived cells limited
  20. 2022 Medium

    Structural modeling and mutagenesis suggested HLA-C interacts with PCSK9 via an R-X-E motif engaging the CHRD M2 subdomain, potentially serving as 'protein X' that escorts PCSK9–LDLR complexes to degradation, linking MHC class I to lipid metabolism.

    Evidence X-ray crystallography of CHRD, atomic modeling, site-directed mutagenesis, bio-layer interferometry, SAXS

    PMID:36566984

    Open questions at the time
    • Direct HLA-C–PCSK9 biochemical interaction not demonstrated with purified proteins
    • Functional impact on LDLR degradation via HLA-C not shown in loss-of-function experiment
    • Specificity for HLA-C versus other MHC-I molecules not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the full structural basis of KIR recognition of C2-group HLA-C allotypes, the relative contributions of promoter, miR-148a, and ERAP1 regulation to HLA-C surface expression in different cell types, the precise degradation pathway used by Vpu for HLA-C downregulation, and whether HLA-C genuinely functions as a PCSK9 co-receptor for LDLR degradation in vivo.
  • No crystal structure of KIR with C2-group HLA-C
  • Integrated quantitative model of HLA-C expression regulation lacking
  • Vpu-mediated HLA-C degradation pathway mechanistically unresolved
  • PCSK9–HLA-C interaction requires direct biochemical demonstration

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0005198 structural molecule activity 2 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 2 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 2
Partners
B2MCALRCD160ERAP1KIR2DL2KIR2DL3TAP1TAPBP
Complex memberships
HLA-C–β2-microglobulin heterodimerMHC class I peptide-loading complex (calreticulin–tapasin–TAP)

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1977 HLA-C (HLA-CW2) was shown to be a glycosylated polypeptide of ~43 kDa that is noncovalently associated with beta2-microglobulin, structurally homologous to HLA-A and HLA-B antigens, with some heterogeneity in its carbohydrate moiety and lower cell-surface expression levels compared to HLA-A and HLA-B. Biochemical fractionation, lectin-Sepharose adsorption, sedimentation analysis European journal of immunology High 332508
1993 HLA-C alleles are the dominant inhibitory ligands protecting target cells from NK cell-mediated lysis: alleles encoding Asn-77-Lys-80 (C2 group, e.g. Cw4, Cw5, Cw6) inhibit NK1-specific NK cells, whereas alleles encoding Ser-77-Asn-80 (C1 group, e.g. Cw1, Cw7, Cw13) protect from NK2-specific NK cells, as directly demonstrated by HLA-C transfection into class I-deleted cell lines. HLA-C allele transfection into class I-deleted mutant cell lines, NK cell cytotoxicity assays Proceedings of the National Academy of Sciences of the United States of America High 8265660
1995 NK cell p58 receptors for HLA-C (EB6/GL183) exist in two biochemically distinct forms: a ~58 kDa inhibitory form (p58) and a ~50 kDa activatory form (p50), differing in molecular mass but not solely due to differential glycosylation; cross-linking of p50 triggers cytolytic activity and Ca2+ influx whereas p58 cross-linking inhibits lysis without Ca2+ influx, and p50-bearing NK clones lyse HLA-Cw4+ targets upon specific HLA-C recognition. Biochemical analysis (deglycosylation, peptide mapping, 2D mapping), anti-receptor mAb cross-linking, Ca2+ flux, NK cytotoxicity assays, LCL721.221/Cw4 transfectant targets The Journal of experimental medicine High 7650491
1997 HLA-C binds to NK inhibitory receptors (KIR/NKIR) with extremely fast association and dissociation kinetics (among the fastest immune interactions characterized), as measured using soluble recombinant HLA-C molecules and recombinant NKIR proteins. Surface plasmon resonance / kinetic binding assays using soluble recombinant HLA-C and KIR proteins Immunity High 9768753
1997 Recombinant soluble p58 KIRs (KIR-K6 and KIR-K7) bind soluble HLA-Cw3 and HLA-Cw6 molecules directly, and this binding is influenced by the antigenic peptide bound to the MHC, indicating peptide-dependence of KIR-HLA-C recognition; both Ig domains of p58 are required for HLA-C binding. Native gel shift assay with recombinant soluble proteins, domain-deletion analysis Journal of immunology High 9378975
1988 HLA-Cw3 expressed in transgenic mice functions as a transplantation antigen capable of inducing rapid skin graft rejection and serves as an MHC restriction molecule for cytotoxic T lymphocyte responses to influenza and Sendai virus, demonstrating that HLA-C has immunological functions comparable to HLA-A and HLA-B. HLA-Cw3 transgenic mouse model, skin graft rejection assays, virus-specific CTL assays Proceedings of the National Academy of Sciences of the United States of America High 2840670
2000 HLA-C protein is expressed on the surface of extravillous trophoblast cells in association with beta2-microglobulin, with both paternal and maternal alleles transcribed; cell-surface HLA-C (but not HLA-G) is upregulated by IFN-γ treatment, demonstrating differential cytokine regulation. Flow cytometric sorting of first-trimester trophoblast, cDNA sequencing, biochemical analysis, flow cytometry, immunohistology Placenta High 10833373
2000 Two clusters of polymorphic residues on KIR2D molecules define group allotype specificity for HLA-C binding: multiple polymorphic residues contribute to the HLA-C binding site, with specific residues determining whether a KIR binds C1 or C2 group alleles. Site-directed mutagenesis of KIR chimeric proteins (KIR extracellular domain fused to CD3-ζ tail), signaling assays, HLA-C binding specificity analysis European journal of immunology High 10820396
2002 The CD160 receptor expressed on circulating CD56dim NK cells directly interacts with HLA-C molecules expressed on K562 cells and triggers NK cell cytotoxicity; direct protein-protein interaction between recombinant soluble HLA-Cw3 and CD160 was demonstrated. Anti-CD160 mAb blocking of NK cytotoxicity, recombinant soluble protein binding assay (direct HLA-Cw3/CD160 interaction), NK cell functional assays Proceedings of the National Academy of Sciences of the United States of America High 12486241
2007 HLA-C heavy chains accumulate intracellularly in two forms (free of and associated with β2-microglobulin) due to a unique KYRV motif at residues 66-76 of the α1-domain helix that causes poor assembly, post-assembly instability, reduced peptide-binding groove plasticity, and association with dedicated chaperones TAP and tapasin; this locus-specific bottleneck renders HLA-C peptide-selective (rather than peptide-unreceptive) and contributes to its preferential role as an NK cell ligand. Pulse-labeling experiments, co-immunoprecipitation with anti-TAP/tapasin antibodies, molecular dynamics simulation, in vitro assembly in T2 and 721.220 cell extracts, reactivity with conformation-specific antibodies The Journal of biological chemistry High 17956861
2008 KIR2DL2 is a stronger receptor for HLA-C than KIR2DL3 due to synergistic polymorphism at two positions distal to the ligand-binding site (Pro16Arg in D1 and Arg148Cys in D2); neither substitution alone is sufficient—only the combination increases avidity, likely by altering the hinge angle between the two Ig domains and changing the relative orientation of the ligand-binding site. Mutagenesis of recombinant KIR proteins, functional binding assays to 93 HLA isoforms, site-directed mutagenesis Journal of immunology High 18322206
2008 HLA-C molecules associated with HIV-1 gp120 on infected cell surfaces and virion-associated HLA-C increases the infectivity of both R5 and X4 HIV-1 viruses; co-purification of HLA-C with gp120 from fusion complexes was demonstrated. siRNA knockdown of HLA-C, syncytia formation assays, pseudovirus infectivity assays, co-purification of fusion complexes Retrovirology High 18673537
2011 Differential surface expression of HLA-C allotypes is mediated by binding of microRNA miR-148a to the 3′ UTR of HLA-C mRNA: alleles susceptible to miR-148a binding have lower surface expression; the common ancestor of all HLA-C alleles was suppressed by miR-148a, and escape alleles arose ~3–5 million years ago via sequence exchange with an HLA-B allele, with selective pressure favoring spread of the escape variants. Molecular evolutionary analysis, miRNA binding site characterization, sequence exchange mapping American journal of human genetics Medium 21907013
2013 KIR2DL3*005 has markedly increased affinity and avidity for HLA-C ligands compared to other KIR2DL3 alleles due to a combination of Arg at residue 11 and Glu at residue 35 (distal to the KIR/HLA-C interface), likely by shifting the interdomain hinge angle toward the KIR2DL2 configuration; this confers stronger inhibition of NK cell IFN-γ production. Surface plasmon resonance, KIR binding panel assay, site-directed mutagenesis, NK cell functional assay (IFN-γ production by KHYG-1 cells), flow cytometry Journal of immunology High 23686481
2016 HIV-1 Vpu (not Nef) mediates downregulation of HLA-C on infected cells in most primary HIV-1 isolates; HLA-C downregulation by Vpu reduces the ability of HLA-C-restricted CTLs to suppress viral replication in CD4+ cells in vitro; HLA-A and HLA-B are unaffected by Vpu. Primary HIV-1 clone panel, Vpu mutant viruses, HLA-C surface expression flow cytometry, CTL suppression of viral replication assays in CD4+ cells Cell host & microbe High 27173934
2017 HIV-1 Env (gp120) specifically associates with HLA-C free chains (not bound to β2-microglobulin) at the cell membrane; HIV-1 infection increases the amount of HLA-C free chains on infected cell membranes; the enhanced infectivity conferred by HLA-C requires prior correct assembly with β2m before HLA-C free chains can associate with Env, and pseudoviruses produced from HLA-C-silenced or β2m-absent cells are less infectious. β2m-free HLA-C chain detection, HIV-1 Env pseudovirus infectivity assays, β2m knockout/knockdown experiments, cell-surface biochemistry Scientific reports Medium 28051183
2018 HLA-C downregulation by HIV-1 Vpu adapts to host HLA-C genotype: HLA-C alleles differ in the immune pressure they exert, and individuals with higher HLA-C expression favor greater viral downregulation; 5 residues in the transmembrane region of Vpu and 4 residues in the transmembrane domain of HLA-C determine Vpu-HLA-C interactions. Primary viral isolate panel (128 replication-competent viruses), Vpu mutant analysis, cloning and expression of Vpu from 195 treatment-naïve individuals, transmembrane domain mutagenesis PLoS pathogens High 30180214
2018 An NK cell-specific HLA-C promoter drives an array of alternative transcripts with variable intron/exon content; skipping of the first coding exon generates untranslatable mRNAs, and the proportion of these decreases as NK cells mature, correlating with increased HLA-C protein expression; polymorphism in a key Ets-binding site of the NK promoter generates HLA-C alleles with reduced promoter activity, resulting in lower HLA-C expression and increased NK cell functional activity. Transcript analysis (alternative splicing), promoter reporter assays (Ets-binding site mutagenesis), NK cell maturation tracking, flow cytometry of HLA-C protein levels PLoS genetics High 29329284
2021 Crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope revealed that KIR2DL2 differs from KIR2DL3 in its docking modality over HLA-C*07:02; mutagenesis assays showed differences in mechanism of HLA-C1 allotype recognition, with HLA-C1 allotypes differing markedly in capacity to inhibit NK cell activation; KIR2DS2 contributes to functional differences alongside KIR2DL2/3 binding geometries. X-ray crystallography, site-directed mutagenesis, primary NK cell inhibition assays Nature communications High 33846289
2021 ERAP1 generates the causative melanocyte autoantigen (ADAMTSL5-derived peptide) for HLA-C*06:02 presentation in psoriasis by trimming N-terminally elongated peptide precursors to the appropriate length; an ERAP1 psoriasis-risk haplotype produces the autoantigen more efficiently, increases HLA-C surface expression, and enhances stimulation of psoriatic TCR by melanocytes; HLA-C surface expression decreases significantly more than overall HLA class I upon ERAP1 knockout, demonstrating a specific dependency of HLA-C on ERAP1. Genetically modified cell lines with ERAP1 risk/protective haplotypes, ERAP1 knockout, TCR activation assay with autoreactive psoriatic TCR, flow cytometry of HLA-C surface expression Journal of immunology High 34580106
2011 HLA-Cw*0602 allele-specific regulatory variants virtually abolish the HLA-C transcriptional response to TNF-α (rs2524094) and IFN-γ (rs10657191), as demonstrated by reporter assays and validated in primary keratinocytes; HLA-Cw*0602 transcripts are not upregulated in psoriatic skin lesions despite elevated TNF-α, indicating allele-specific cytokine unresponsiveness. Promoter reporter assays, primary keratinocyte cytokine treatment, qRT-PCR in psoriatic skin The Journal of investigative dermatology Medium 22113476
1996 HIV-1 Nef stimulates endocytosis and intracellular accumulation of surface MHC class I molecules (including HLA-A and HLA-B) in lymphoid, monocytic and epithelial cells; MHC-I synthesis and ER/cis-Golgi transport are unaffected, but surface molecules are rapidly internalized into endosomal vesicles and degraded. (Note: original Nef paper does not distinguish HLA-C from HLA-A/B, but subsequent work established HLA-C is NOT efficiently downregulated by Nef—see Vpu entries above.) Nef expression in multiple cell lines, pulse-chase analysis, immunofluorescence/endosomal fractionation Nature medicine Medium 8612235
1996 Assembly of MHC class I heavy chain-β2m dimers in the ER requires calreticulin (which binds class I-β2m dimers) and the novel glycoprotein tapasin (which bridges class I-β2m-calreticulin complexes to TAP), establishing the peptide-loading complex; this mechanism applies to HLA-C as one of the class I molecules assembled via this pathway. Co-immunoprecipitation, biochemical fractionation, characterization of .220 (tapasin-deficient) mutant cells Immunity High 8769474
2022 HLA-C interacts with PCSK9 via an R-X-E motif in the HLA-C transmembrane/intracellular region engaging the M2 subdomain of PCSK9's CHRD; modeling and mutagenesis identified Glu567 and Arg549 as critical M2 residues binding HLA-C, and these same residues are required for PCSK9-induced LDLR degradation, suggesting HLA-C (or a similar MHC-I member) may act as 'protein X' escorting the PCSK9-LDLR complex to degradation compartments. X-ray crystallography of CHRD-nanobody complex (2.2 Å), atomic modeling, site-directed mutagenesis, bio-layer interferometry, SAXS, immunocytochemistry, deep mutational scanning Molecular metabolism Medium 36566984

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2009 Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 3645 19571811
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nature genetics 1160 19169254
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2007 A whole-genome association study of major determinants for host control of HIV-1. Science (New York, N.Y.) 1010 17641165
2002 Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet (London, England) 1007 11888582
2007 High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 1004 17785583
2010 The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science (New York, N.Y.) 985 21051598
2005 HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proceedings of the National Academy of Sciences of the United States of America 955 15743917
2004 HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science (New York, N.Y.) 917 15297676
1996 Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nature medicine 874 8612235
2010 A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nature genetics 843 20953190
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
1999 A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. The Journal of experimental medicine 559 10190900
1996 Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP. Immunity 555 8769474
2015 SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 548 25561175
2004 Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood 544 15191952
2008 A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS genetics 542 18369459
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2018 The shieldin complex mediates 53BP1-dependent DNA repair. Nature 502 30022168
2013 Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nature genetics 496 23563607
2006 Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. American journal of human genetics 463 16642438
1995 Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. The Journal of experimental medicine 423 7650491
1993 HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells. Proceedings of the National Academy of Sciences of the United States of America 404 8265660
2008 Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3. Journal of immunology (Baltimore, Md. : 1950) 324 18322206
2002 Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles. Journal of immunology (Baltimore, Md. : 1950) 260 12218090
2000 Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C. American journal of human genetics 195 10801386
2000 Surface expression of HLA-C antigen by human extravillous trophoblast. Placenta 192 10833373
2010 HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 165 20870028
1977 Molecular structure of human histocompatibility antigens: the HLA-C series. European journal of immunology 157 332508
2003 Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis. The Journal of investigative dermatology 140 12648227
2011 Maternal KIR and fetal HLA-C: a fine balance. Journal of leukocyte biology 131 21873457
2016 HIV-1 Vpu Mediates HLA-C Downregulation. Cell host & microbe 118 27173934
2002 Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus. American journal of human genetics 111 12148091
2000 A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele. Human molecular genetics 109 10888604
2002 Engagement of CD160 receptor by HLA-C is a triggering mechanism used by circulating natural killer (NK) cells to mediate cytotoxicity. Proceedings of the National Academy of Sciences of the United States of America 108 12486241
2002 Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus. Human molecular genetics 105 11875053
2001 Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci. Journal of medical genetics 101 11134234
1998 Kinetics of interaction of HLA-C ligands with natural killer cell inhibitory receptors. Immunity 101 9768753
2019 The Dual Role of HLA-C in Tolerance and Immunity at the Maternal-Fetal Interface. Frontiers in immunology 100 31921098
2015 Polymorphic HLA-C Receptors Balance the Functional Characteristics of KIR Haplotypes. Journal of immunology (Baltimore, Md. : 1950) 100 26311903
1988 Immunological function of HLA-C antigens in HLA-Cw3 transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 100 2840670
2002 Evidence for a major psoriasis susceptibility locus at 6p21(PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese hans. The Journal of investigative dermatology 83 12485440
2000 HLA-C and guttate psoriasis. The British journal of dermatology 80 11122018
2017 Missing or altered self: human NK cell receptors that recognize HLA-C. Immunogenetics 77 28695291
2010 Killer immunoglobulin-like receptors (KIRs) and HLA-C allorecognition patterns implicative of dominant activation of natural killer cells contribute to recurrent miscarriages. Human reproduction (Oxford, England) 75 21159685
2005 The major psoriasis susceptibility locus PSORS1 is not a risk factor for late-onset psoriasis. The Journal of investigative dermatology 71 15654960
2016 Variation of maternal KIR and fetal HLA-C genes in reproductive failure: too early for clinical intervention. Reproductive biomedicine online 69 27751789
2007 TNF polymorphisms in psoriasis: association of psoriatic arthritis with the promoter polymorphism TNF*-857 independent of the PSORS1 risk allele. Arthritis and rheumatism 67 17530646
2010 Coevolution of killer cell Ig-like receptors with HLA-C to become the major variable regulators of human NK cells. Journal of immunology (Baltimore, Md. : 1950) 64 20805421
2013 Allelic variation in KIR2DL3 generates a KIR2DL2-like receptor with increased binding to its HLA-C ligand. Journal of immunology (Baltimore, Md. : 1950) 60 23686481
2005 Distinct HLA-C/KIR genotype profile associates with guttate psoriasis. The Journal of investigative dermatology 59 16185272
1994 SSOP typing of the Tenth International Histocompatibility Workshop reference cell lines for HLA-C alleles. Tissue antigens 56 7839350
2011 The emerging role of HLA-C in HIV-1 infection. Immunology 53 21896007
2012 Genetic association with ERAP1 in psoriasis is confined to disease onset after puberty and not dependent on HLA-C*06. The Journal of investigative dermatology 52 22931917
2006 HLA-C locus alleles may modulate the clinical expression of psoriatic arthritis. Arthritis research & therapy 49 17166285
2020 Population Difference in Allele Frequency of HLA-C*05 and Its Correlation with COVID-19 Mortality. Viruses 48 33233780
2010 Detection of antibodies against HLA-C epitopes in patients with rejected kidney transplants. Transplant immunology 47 21185937
2021 Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C. Nature communications 45 33846289
2017 KIR2DS5 allotypes that recognize the C2 epitope of HLA-C are common among Africans and absent from Europeans. Immunity, inflammation and disease 44 28685972
2004 Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosin gene (CDSN). American journal of human genetics 43 15529278
2011 The molecular origin and consequences of escape from miRNA regulation by HLA-C alleles. American journal of human genetics 42 21907013
1998 A reliable and efficient high resolution typing method for HLA-C using sequence-based typing. Tissue antigens 42 9894855
1997 Molecular basis of HLA-C recognition by p58 natural killer cell inhibitory receptors. Journal of immunology (Baltimore, Md. : 1950) 42 9378975
1976 Cell mediated lympholysis in man. The impact of HLA-C antigens. Tissue antigens 42 59406
2021 ERAP1 Controls the Autoimmune Response against Melanocytes in Psoriasis by Generating the Melanocyte Autoantigen and Regulating Its Amount for HLA-C*06:02 Presentation. Journal of immunology (Baltimore, Md. : 1950) 41 34580106
2017 Melanocytes: Target Cells of an HLA-C*06:02-Restricted Autoimmune Response in Psoriasis. The Journal of investigative dermatology 40 28941475
2014 A comprehensive analysis of constitutive naturally processed and presented HLA-C*04:01 (Cw4)-specific peptides. Tissue antigens 40 24397554
1988 Specific restriction fragment length polymorphism on the HLA-C region and susceptibility to psoriasis vulgaris. The Journal of investigative dermatology 40 2894398
2007 A single bottleneck in HLA-C assembly. The Journal of biological chemistry 39 17956861
2014 Increased frequency and function of KIR2DL1-3⁺ NK cells in primary HIV-1 infection are determined by HLA-C group haplotypes. European journal of immunology 38 25043727
1986 An HLA-C-specific DNA probe. Immunogenetics 38 3456979
2006 HLA-C mismatch is associated with inferior survival after unrelated donor non-myeloablative hematopoietic stem cell transplantation. Bone marrow transplantation 37 16532020
1997 HLA-C genes and susceptibility to type 1 autoimmune hepatitis. Hepatology (Baltimore, Md.) 35 9328330
2012 HLA-C and HIV-1: friends or foes? Retrovirology 32 22571741
2008 The PSORS1 locus gene CCHCR1 affects keratinocyte proliferation in transgenic mice. Human molecular genetics 32 18174193
2020 The Roles of Uterine Natural Killer (NK) Cells and KIR/HLA-C Combination in the Development of Preeclampsia: A Systematic Review. BioMed research international 31 32309433
2014 Association of maternal KIR and fetal HLA-C genes with the risk of preeclampsia in the Chinese Han population. Placenta 31 24951171
2009 Characterisation of psoriasis susceptibility locus 6 (PSORS6) in patients with early onset psoriasis and evidence for interaction with PSORS1. Journal of medical genetics 31 19525279
2004 Transgenic mouse models support HCR as an effector gene in the PSORS1 locus. Human molecular genetics 30 15190014
2021 The New Kid on the Block: HLA-C, a Key Regulator of Natural Killer Cells in Viral Immunity. Cells 28 34831331
1996 A correlation between HLA-C matching and donor antirecipient CTL precursor frequency in bone marrow transplantation. Transplantation 27 8629311
2010 Characterization of an HLA-C-restricted CTL response in chronic HIV infection. European journal of immunology 26 20104487
2004 Isolated HLA-C mismatches in unrelated donor transplantation for CML. Bone marrow transplantation 26 15195077
2019 HLA-C: An Accomplice in Rheumatic Diseases. ACR open rheumatology 25 31777841
2018 Identification of an elaborate NK-specific system regulating HLA-C expression. PLoS genetics 25 29329284
2018 HLA-C downregulation by HIV-1 adapts to host HLA genotype. PLoS pathogens 25 30180214
2002 Molecular diversity of the HLA-C gene identified in a caucasian population. Human immunology 25 12072195
2020 Tuning of human NK cells by endogenous HLA-C expression. Immunogenetics 24 32219494
2010 HLA-C C1C2 heterozygosity may protect women bearing the killer immunoglobulin-like receptor AA genotype from spontaneous abortion. Journal of reproductive immunology 24 21134695
2017 ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population. Innate immunity 23 28651467
2014 Indirectly Recognized HLA-C Mismatches and Their Potential Role in Transplant Outcome. Frontiers in immunology 23 24860572
2014 HLA-C Incompatibilities in Allogeneic Unrelated Hematopoietic Stem Cell Transplantation. Frontiers in immunology 22 24904572
2011 Allele-specific cytokine responses at the HLA-C locus: implications for psoriasis. The Journal of investigative dermatology 22 22113476
1978 "Silent" alleles at the HLA-C locus. Journal of immunology (Baltimore, Md. : 1950) 22 79614
2011 Tumor necrosis factor promoter polymorphism TNF*-857 is a risk allele for psoriatic arthritis independent of the PSORS1 locus. Arthritis and rheumatism 21 22127698
2010 Counteraction of HLA-C-mediated immune control of HIV-1 by Nef. Journal of virology 21 20463068
2021 ERAP, KIR, and HLA-C Profile in Recurrent Implantation Failure. Frontiers in immunology 20 34745129
2017 Associations of ERAP1 coding variants and domain specific interaction with HLA-C∗06 in the early onset psoriasis patients of India. Human immunology 20 28867178
2017 HLA-C*17, DQB1*03:01, DQA1*01:03 and DQA1*05:05 Alleles Associated to Bullous Pemphigoid in Brazilian Population. Annals of dermatology 20 29386826
2013 Association analysis of the HLA-C gene in Japanese alopecia areata. Immunogenetics 20 23588886
2018 Cross-Reactivity of Virus-Specific CD8+ T Cells Against Allogeneic HLA-C: Possible Implications for Pregnancy Outcome. Frontiers in immunology 19 30574149
2015 Uptake of CCR7 by KIR2DS4⁺ NK cells is induced upon recognition of certain HLA-C alleles. Journal of immunology research 19 25961063
2010 Comparison of MHC class I risk haplotypes in Thai and Caucasian psoriatics shows locus heterogeneity at PSORS1. Tissue antigens 19 20604894
1990 Functional expression of HLA-C blank antigens on human blood lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 19 2246509
2023 "HLA-C: evolution, epigenetics, and pathological implications in the major histocompatibility complex". Frontiers in genetics 18 37465164
2016 Hypermethylation of HLA-C may be an epigenetic marker in psoriasis. Journal of dermatological science 18 27132688
2008 Association analysis of the skin barrier gene cystatin A at the PSORS5 locus in psoriatic patients: evidence for interaction between PSORS1 and PSORS5. European journal of human genetics : EJHG 18 18364739
2004 Role of a KIR/HLA-C allorecognition system in pregnancy. Journal of reproductive immunology 18 15288178
2003 Psoriasis vulgaris and psoriatic arthritis share a 100 kb susceptibility region telomeric to HLA-C. Rheumatology (Oxford, England) 17 12730526
2000 Definition of polymorphic residues on killer Ig-like receptor proteins which contribute to the HLA-C binding site. European journal of immunology 17 10820396
2019 Identification of Immunodominant HIV-1 Epitopes Presented by HLA-C*12:02, a Protective Allele, Using an Immunopeptidomics Approach. Journal of virology 16 31217245
2011 A study of KIR genes and HLA-C in Vogt-Koyanagi-Harada disease in Saudi Arabia. Molecular vision 16 22219647
2022 Association between HLA-C alleles and COVID-19 severity in a pilot study with a Spanish Mediterranean Caucasian cohort. PloS one 15 35960731
2017 HIV-1 Env associates with HLA-C free-chains at the cell membrane modulating viral infectivity. Scientific reports 15 28051183
2014 Conjunctival scarring in trachoma is associated with the HLA-C ligand of KIR and is exacerbated by heterozygosity at KIR2DL2/KIR2DL3. PLoS neglected tropical diseases 15 24651768
2005 Fine mapping of the psoriasis susceptibility gene PSORS1: a reassessment of risk associated with a putative risk haplotype lacking HLA-Cw6. The Journal of investigative dermatology 15 15854032
2022 HLA-B*07:02 and HLA-C*07:02 are associated with trimethoprim-sulfamethoxazole respiratory failure. The pharmacogenomics journal 14 35169303
2022 Functional HLA-C expressing trophoblast spheroids as a model to study placental-maternal immune interactions during human implantation. Scientific reports 14 35715452
2022 Molecular interactions of PCSK9 with an inhibitory nanobody, CAP1 and HLA-C: Functional regulation of LDLR levels. Molecular metabolism 14 36566984
2012 The impact of HLA-C matching depends on the C1/C2 KIR ligand status in unrelated hematopoietic stem cell transplantation. Immunogenetics 14 22923051
2008 HLA-C increases HIV-1 infectivity and is associated with gp120. Retrovirology 14 18673537