Structure of HLA-A*0301 in complex with a peptide of proteolipid protein: insights into the role of HLA-A alleles in susceptibility to multiple sclerosis.

TY - JOUR

T1 - Structure of HLA-A*0301 in complex with a peptide of proteolipid protein: insights into the role of HLA-A alleles in susceptibility to multiple sclerosis.

AU - McMahon, Róisín M

AU - Friis, Lone

AU - Siebold, Christian

AU - Friese, Manuel A.

AU - Fugger, Lars

AU - Jones, E Yvonne

PY - 2011

Y1 - 2011

N2 - The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7?Å resolution. HLA-A3 is a predisposing allele for multiple sclerosis (MS), an autoimmune disease of the central nervous system. The KLIETYFSK peptide is a naturally processed epitope of proteolipid protein, a myelin protein and candidate target for immune-mediated myelin destruction in MS. Comparison of the structure of HLA-A3 with that of HLA-A2, an MHC class I molecule which is protective against MS, indicates that both MHC class I molecules present very similar faces for T-cell receptor recognition whilst differing in the specificity of their peptide-binding grooves. These characteristics may underlie the opposing (predisposing versus protective) associations that they exhibit both in humans and in mouse models of MS-like disease. Furthermore, subtle alterations within the peptide-binding groove of HLA-A3 and other A3-like MHC class I molecules, members of the so-called A3 superfamily, may be sufficient to alter their presentation of autoantigen peptides such as KLIETYFSK. This in turn may modulate their contribution to the associated risk of autoimmune disease.

AB - The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7?Å resolution. HLA-A3 is a predisposing allele for multiple sclerosis (MS), an autoimmune disease of the central nervous system. The KLIETYFSK peptide is a naturally processed epitope of proteolipid protein, a myelin protein and candidate target for immune-mediated myelin destruction in MS. Comparison of the structure of HLA-A3 with that of HLA-A2, an MHC class I molecule which is protective against MS, indicates that both MHC class I molecules present very similar faces for T-cell receptor recognition whilst differing in the specificity of their peptide-binding grooves. These characteristics may underlie the opposing (predisposing versus protective) associations that they exhibit both in humans and in mouse models of MS-like disease. Furthermore, subtle alterations within the peptide-binding groove of HLA-A3 and other A3-like MHC class I molecules, members of the so-called A3 superfamily, may be sufficient to alter their presentation of autoantigen peptides such as KLIETYFSK. This in turn may modulate their contribution to the associated risk of autoimmune disease.

KW - Humans

KW - Amino Acid Sequence

KW - Binding Sites

KW - Models, Molecular

KW - Crystallography, X-Ray

KW - HLA-A2 Antigen/chemistry/metabolism

KW - HLA-A3 Antigen/chemistry/metabolism

KW - Multiple Sclerosis/metabolism

KW - Peptides/chemistry/metabolism

KW - Proteolipids/chemistry/metabolism

KW - Humans

KW - Amino Acid Sequence

KW - Binding Sites

KW - Models, Molecular

KW - Crystallography, X-Ray

KW - HLA-A2 Antigen/chemistry/metabolism

KW - HLA-A3 Antigen/chemistry/metabolism

KW - Multiple Sclerosis/metabolism

KW - Peptides/chemistry/metabolism

KW - Proteolipids/chemistry/metabolism

M3 - SCORING: Journal article

VL - 67

SP - 447

EP - 454

JO - ACTA CRYSTALLOGR D

JF - ACTA CRYSTALLOGR D

SN - 2059-7983

IS - Pt 5

M1 - Pt 5

ER -