6p23 | pdb_00006p23

Structure of a nested set of N-terminally extended MHC I-peptides provide novel insights into antigen processing presentation

spinqualitylabelsall models 6p23, resolution 1.59Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6p23 is a 3 chain structure with sequence from Homo sapiens and Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.595Å Ligands: MAA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease HLAB_HUMAN Prediction of allopurinol toxicity;NON RARE IN EUROPE: Ankylosing spondylitis;Prediction of flucloxacilline toxicity;Giant cell arteritis;Takayasu arteritis;Reactive arthritis;Behcet disease;Stevens-Johnson syndrome;Prediction of phenytoin or carbamazepine toxicity;Pulmonary arterial hypertension associated with connective tissue disease;Prediction of abacavir toxicity. Disease susceptibility is associated with variants affecting the gene represented in this entry. Increased susceptibility to Stevens-Johnson syndrome is conferred by allele B*15:02. Disease susceptibility is associated with variants affecting the gene represented in this entry. A restricted number of HLA-B*27 subtypes can be associated with ankylosing spondylitis and other B*27-related diseases, and an elevated frequency of the B*27:02 allele in ankylosing spondylitis patients is identified. The allele B*27:07 seems to have a protective role in some populations because it was found only in the healthy controls. There is evidence that HLA-B*51 is associated with susceptibility to Behcet disease (BD). However, it is not certain whether HLA-B*51 itself or a closely linked gene is responsible for susceptibility. The world distribution of HLA-B*51 in healthy people corresponds to the global distribution of BD; in Southern hemisphere countries (Africa, South Pacific, etc.) and in some parts of Europe, the prevalence of HLA-B*51 in healthy people is low or null, corresponding to a low prevalence of BD. The wide variation that exists in the relative risk of HLA-B*51 would support other nongenetic risk factors. The presence of allele B*57:01 is associated with increased susceptibility to abacavir hypersensitivity [MIM:142830 in HIV-1 patients. Allele group B*08 is associated with increased susceptibility to rheumatoid arthritis, where affected individuals have antibodies to cyclic citrullinated peptide (anti-CCP-positive rheumatoid arthritis). Function HLAB_HUMAN Antigen-presenting major histocompatibility complex class I (MHCI) molecule. In complex with B2M/beta 2 microglobulin displays primarily viral and tumor-derived peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-B-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected or transformed cells (PubMed:25808313, PubMed:29531227, PubMed:9620674, PubMed:23209413). May also present self-peptides derived from the signal sequence of secreted or membrane proteins, although T cells specific for these peptides are usually inactivated to prevent autoreactivity (PubMed:7743181, PubMed:18991276). 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 (PubMed:29531227, PubMed:9620674, PubMed:24600035). Typically presents intracellular peptide antigens of 8 to 13 amino acids that arise from cytosolic proteolysis via constitutive proteasome and IFNG-induced immunoproteasome (PubMed:23209413). Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9 (PubMed:25808313, PubMed:29531227). Allele B*07:02: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and mainly a Leu anchor residue at the C-terminus (PubMed:7743181). Presents a long peptide (APRGPHGGAASGL) derived from the cancer-testis antigen CTAG1A/NY-ESO-1, eliciting a polyclonal CD8-positive T cell response against tumor cells (PubMed:29531227). Presents viral epitopes derived from HIV-1 gag-pol (TPQDLNTML) and Nef (RPQVPLRPM) (PubMed:25808313). Presents an immunodominant epitope derived from SARS-CoV-2 N/nucleoprotein (SPRWYFYYL) (PubMed:32887977). Displays self-peptides including a peptide derived from the signal sequence of HLA-DPB1 (APRTVALTA) (PubMed:7743181). Allele B*08:01: Presents to CD8-positive T cells viral epitopes derived from EBV/HHV-4 EBNA3 (QAKWRLQTL), eliciting cytotoxic T cell response. Allele B*13:02: Presents multiple HIV-1 epitopes derived from gag (RQANFLGKI, GQMREPRGSDI), nef (RQDILDLWI), gag-pol (RQYDQILIE, GQGQWTYQI) and rev (LQLPPLERL), all having in common a Gln residue at position 2 and mainly hydrophobic amino acids Leu, Ile or Val at the C-terminus. Associated with succesful control of HIV-1 infection. Allele B*18:01: Preferentially presents octomeric and nonameric peptides sharing a common motif, namely a Glu at position 2 and Phe or Tyr anchor residues at the C-terminus (PubMed:14978097, PubMed:23749632, PubMed:18991276). Presents an EBV/HHV-4 epitope derived from BZLF1 (SELEIKRY) (PubMed:23749632). May present to CD8-positive T cells an antigenic peptide derived from MAGEA3 (MEVDPIGHLY), triggering an anti-tumor immune response (PubMed:12366779). May display a broad repertoire of self-peptides with a preference for peptides derived from RNA-binding proteins (PubMed:14978097). Allele B*27:05: Presents to CD8-positive T cells immunodominant viral epitopes derived from HCV POLG (ARMILMTHF), HIV-1 gag (KRWIILGLNK), IAV NP (SRYWAIRTR), SARS-CoV-2 N/nucleoprotein (QRNAPRITF), EBV/HHV-4 EBNA4 (HRCQAIRKK) and EBV/HHV-4 EBNA6 (RRIYDLIEL), confering longterm protection against viral infection (PubMed:19139562, PubMed:18385228, PubMed:15113903, PubMed:9620674, PubMed:32887977). Can present self-peptides derived from cytosolic and nuclear proteins. All peptides carry an Arg at position 2 (PubMed:1922338). The peptide-bound form interacts with NK cell inhibitory receptor KIR3DL1 and inhibits NK cell activation in a peptide-specific way, being particularly sensitive to the nature of the amino acid side chain at position 8 of the antigenic peptide (PubMed:8879234, PubMed:15657948). KIR3DL1 fails to recognize HLA-B*27:05 in complex with B2M and EBV/HHV-4 EBNA6 (RRIYDLIEL) peptide, which can lead to increased activation of NK cells during infection (PubMed:15657948). May present an altered repertoire of peptides in the absence of TAP1-TAP2 and TAPBPL (PubMed:9620674). Allele B*40:01: Presents immunodominant viral epitopes derived from EBV/HHV-4 LMP2 (IEDPPFNSL) and SARS-CoV-2 N/nucleoprotein (MEVTPSGTWL), triggering memory CD8-positive T cell response (PubMed:18991276, PubMed:32887977). Displays self-peptides sharing a signature motif, namely a Glu at position 2 and a Leu anchor residue at the C-terminus (PubMed:18991276). Allele B*41:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ala or Pro anchor residues at the C-terminus. Allele B*44:02: Presents immunodominant viral epitopes derived from EBV/HHV-4 EBNA4 (VEITPYKPTW) and EBNA6 (AEGGVGWRHW, EENLLDFVRF), triggering memory CD8-positive T cell response (PubMed:9620674, PubMed:18991276). Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Phe, Tyr or Trp anchor residues at the C-terminus (PubMed:18991276). Allele B*45:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ala or Pro anchor residues at the C-terminus. Allele B*46:01: Preferentially presents nonameric peptides sharing a signature motif, namely Ala and Leu at position 2 and Tyr, Phe, Leu, or Met anchor residues at the C-terminus. The peptide-bound form interacts with KIR2DL3 and inhibits NK cell cytotoxic response in a peptide-specific way. Allele B*47:01: Displays self-peptides sharing a signature motif, namely an Asp at position 2 and Leu or Met anchor residues at the C-terminus. Allele B*49:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ile or Val anchor residues at the C-terminus. Allele B*50:01: Displays self-peptides sharing a signature motif, namely a Glu at position 2 and Ala or Pro anchor residues at the C-terminus. Allele B*51:01: Presents an octomeric HIV-1 epitope derived from gag-pol (TAFTIPSI) to the public TRAV17/TRBV7-3 TCR clonotype, strongly suppressing HIV-1 replication. Allele B*54:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Ala anchor residue at the C-terminus. Allele B*55:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Ala anchor residue at the C-terminus. Allele B*56:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Ala anchor residue at the C-terminus. Allele B*57:01: The peptide-bound form recognizes KIR3DL1 and inhibits NK cell cytotoxic response. Allele B*67:01: Displays peptides sharing a common signature motif, namely a Pro residue at position 2 and Leu anchor residue at the C-terminus. Publication Abstract from PubMed Endoplasmic reticulum aminopeptidases 1 (ERAP1) and ERAP2 critically shape the major histocompatibility complex I (MHC I) immunopeptidome. The ERAPs remove N-terminal residues from antigenic precursor peptides and generate optimal-length peptides,i.e., 8-10mers, to fit into the MHC class I groove. It is therefore intriguing that MHC class I molecules can present N-terminally extended peptides on the cell surface that can elicit CD8+ T-cell responses. This observation likely reflects gaps in our understanding of how antigens are processed by the ERAP enzymes. To better understand ERAPs' function in antigen processing, here we generated a nested set of N-terminally extended 10-20mer peptides (RA)nAAKKKYCL covalently bound to the human leukocyte antigen (HLA)-B*0801. We used X-ray crystallography, thermostability assessments, and an ERAP1-trimming assay to characterize these complexes. The x-ray structures determined at 1.40-1.65 A resolutions revealed that the residue extensions (RA)nunexpectedly protrude out of the A pocket of HLA-B*0801, whereas the AAKKKYCL core of all peptides adopts similar, bound conformations. HLA-B*0801 residue 62 was critical to open the A pocket. We also show that HLA-B*0801 and antigenic precursor peptides form stable complexes. Finally, ERAP1-mediated trimming of the MHC I-bound peptides required a minimal length of 14 amino acids. We propose a mechanistic model explaining how ERAP1-mediated trimming of MHC I-bound peptides in cells can generate peptides of canonical as well as noncanonical lengths that still serve as stable MHC I ligands. Our results provide a framework to better understand how the ERAP enzymes influence the MHC I immunopeptidome. ERAP1 enzyme-mediated trimming and structural analyses of MHC I--bound precursor peptides yield novel insights into antigen processing and presentation.,Li L, Batliwala M, Bouvier M J Biol Chem. 2019 Oct 10. pii: RA119.010102. doi: 10.1074/jbc.RA119.010102. PMID:31601650 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-2 microglobulin 3D structures MHC 3D structures MHC I 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA