The molecular basis for peptide repertoire selection in the human leucocyte antigen (HLA) C∗06: 02 molecule

Jesse I. Mobbs, Patricia T. Illing, Nadine L. Dudek, Andrew G. Brooks, Daniel G. Baker, Anthony W. Purcell, Jamie Rossjohn, Julian P. Vivian

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Human leukocyte antigen (HLA)-C∗06:02 is identified as the allele associated with the highest risk for the development of the autoimmune skin disease psoriasis. However, the diversity and mode of peptide presentation by the HLA-C∗06:02 molecule remains unclear. Here, we describe the endogenous peptide repertoire of ∼3,000 sequences for HLA-C∗06:02 that defines the peptide-binding motif for this HLA allomorph. We found that HLA-C∗06:02 predominantly presents nonamer peptides with dominant arginine anchors at the P2 and P7 positions and a preference for small hydrophobic residues at the C terminus (PΩ). To determine the structural basis of this selectivity, we determined crystal structures of HLA-C∗06:02 in complex with two self-peptides (ARTELYRSL and ARFNDLRFV) and an analogue of a melanocyte autoantigen (ADAMTSL5, VRSRR-abu-LRL) implicated in psoriasis. These structures revealed that HLA-C∗06:02 possesses a deep peptide-binding groove comprising two electronegative Band E-pockets that coincide with the preference for P2 and P7 arginine anchors. The ADAMTSL5 autoantigen possessed a P7-Leu instead of the P7-Arg residue, but nevertheless was accommodated within the HLA-C∗06:02 antigen-binding cleft. Collectively, our results provide the structural basis for understanding peptide repertoire selection in HLA-C∗06:02.

Original languageEnglish
Pages (from-to)17203-17215
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number42
DOIs
Publication statusPublished - 20 Oct 2017

Keywords

  • autoimmunity
  • major histocompatibility complex (MHC)
  • mass spectrometry (MS)
  • psoriasis
  • x-ray crystallography

Cite this

@article{5a83a4d869d1463a810861688549ab37,
title = "The molecular basis for peptide repertoire selection in the human leucocyte antigen (HLA) C∗06: 02 molecule",
abstract = "Human leukocyte antigen (HLA)-C∗06:02 is identified as the allele associated with the highest risk for the development of the autoimmune skin disease psoriasis. However, the diversity and mode of peptide presentation by the HLA-C∗06:02 molecule remains unclear. Here, we describe the endogenous peptide repertoire of ∼3,000 sequences for HLA-C∗06:02 that defines the peptide-binding motif for this HLA allomorph. We found that HLA-C∗06:02 predominantly presents nonamer peptides with dominant arginine anchors at the P2 and P7 positions and a preference for small hydrophobic residues at the C terminus (PΩ). To determine the structural basis of this selectivity, we determined crystal structures of HLA-C∗06:02 in complex with two self-peptides (ARTELYRSL and ARFNDLRFV) and an analogue of a melanocyte autoantigen (ADAMTSL5, VRSRR-abu-LRL) implicated in psoriasis. These structures revealed that HLA-C∗06:02 possesses a deep peptide-binding groove comprising two electronegative Band E-pockets that coincide with the preference for P2 and P7 arginine anchors. The ADAMTSL5 autoantigen possessed a P7-Leu instead of the P7-Arg residue, but nevertheless was accommodated within the HLA-C∗06:02 antigen-binding cleft. Collectively, our results provide the structural basis for understanding peptide repertoire selection in HLA-C∗06:02.",
keywords = "autoimmunity, major histocompatibility complex (MHC), mass spectrometry (MS), psoriasis, x-ray crystallography",
author = "Mobbs, {Jesse I.} and Illing, {Patricia T.} and Dudek, {Nadine L.} and Brooks, {Andrew G.} and Baker, {Daniel G.} and Purcell, {Anthony W.} and Jamie Rossjohn and Vivian, {Julian P.}",
year = "2017",
month = "10",
day = "20",
doi = "10.1074/jbc.M117.806976",
language = "English",
volume = "292",
pages = "17203--17215",
journal = "Journal of Biological Chemistry",
issn = "1083-351X",
publisher = "American Society for Biochemistry and Molecular Biology",
number = "42",

}

The molecular basis for peptide repertoire selection in the human leucocyte antigen (HLA) C∗06 : 02 molecule. / Mobbs, Jesse I.; Illing, Patricia T.; Dudek, Nadine L.; Brooks, Andrew G.; Baker, Daniel G.; Purcell, Anthony W.; Rossjohn, Jamie; Vivian, Julian P.

In: Journal of Biological Chemistry, Vol. 292, No. 42, 20.10.2017, p. 17203-17215.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The molecular basis for peptide repertoire selection in the human leucocyte antigen (HLA) C∗06

T2 - 02 molecule

AU - Mobbs, Jesse I.

AU - Illing, Patricia T.

AU - Dudek, Nadine L.

AU - Brooks, Andrew G.

AU - Baker, Daniel G.

AU - Purcell, Anthony W.

AU - Rossjohn, Jamie

AU - Vivian, Julian P.

PY - 2017/10/20

Y1 - 2017/10/20

N2 - Human leukocyte antigen (HLA)-C∗06:02 is identified as the allele associated with the highest risk for the development of the autoimmune skin disease psoriasis. However, the diversity and mode of peptide presentation by the HLA-C∗06:02 molecule remains unclear. Here, we describe the endogenous peptide repertoire of ∼3,000 sequences for HLA-C∗06:02 that defines the peptide-binding motif for this HLA allomorph. We found that HLA-C∗06:02 predominantly presents nonamer peptides with dominant arginine anchors at the P2 and P7 positions and a preference for small hydrophobic residues at the C terminus (PΩ). To determine the structural basis of this selectivity, we determined crystal structures of HLA-C∗06:02 in complex with two self-peptides (ARTELYRSL and ARFNDLRFV) and an analogue of a melanocyte autoantigen (ADAMTSL5, VRSRR-abu-LRL) implicated in psoriasis. These structures revealed that HLA-C∗06:02 possesses a deep peptide-binding groove comprising two electronegative Band E-pockets that coincide with the preference for P2 and P7 arginine anchors. The ADAMTSL5 autoantigen possessed a P7-Leu instead of the P7-Arg residue, but nevertheless was accommodated within the HLA-C∗06:02 antigen-binding cleft. Collectively, our results provide the structural basis for understanding peptide repertoire selection in HLA-C∗06:02.

AB - Human leukocyte antigen (HLA)-C∗06:02 is identified as the allele associated with the highest risk for the development of the autoimmune skin disease psoriasis. However, the diversity and mode of peptide presentation by the HLA-C∗06:02 molecule remains unclear. Here, we describe the endogenous peptide repertoire of ∼3,000 sequences for HLA-C∗06:02 that defines the peptide-binding motif for this HLA allomorph. We found that HLA-C∗06:02 predominantly presents nonamer peptides with dominant arginine anchors at the P2 and P7 positions and a preference for small hydrophobic residues at the C terminus (PΩ). To determine the structural basis of this selectivity, we determined crystal structures of HLA-C∗06:02 in complex with two self-peptides (ARTELYRSL and ARFNDLRFV) and an analogue of a melanocyte autoantigen (ADAMTSL5, VRSRR-abu-LRL) implicated in psoriasis. These structures revealed that HLA-C∗06:02 possesses a deep peptide-binding groove comprising two electronegative Band E-pockets that coincide with the preference for P2 and P7 arginine anchors. The ADAMTSL5 autoantigen possessed a P7-Leu instead of the P7-Arg residue, but nevertheless was accommodated within the HLA-C∗06:02 antigen-binding cleft. Collectively, our results provide the structural basis for understanding peptide repertoire selection in HLA-C∗06:02.

KW - autoimmunity

KW - major histocompatibility complex (MHC)

KW - mass spectrometry (MS)

KW - psoriasis

KW - x-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=85032036934&partnerID=8YFLogxK

U2 - 10.1074/jbc.M117.806976

DO - 10.1074/jbc.M117.806976

M3 - Article

VL - 292

SP - 17203

EP - 17215

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 42

ER -