The Structure and Stability of the Monomorphic HLA-G Are Influenced by the Nature of the Bound Peptide

• Published in: Journal of molecular biology 2010-03, Vol.397 (2), p.467-480
• Main Authors: Walpole, Nicholas G., Kjer-Nielsen, Lars, Kostenko, Lyudmila, McCluskey, James, Brooks, Andrew G., Rossjohn, Jamie, Clements, Craig S.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; adaptive immunity; antigen presentation; ANTIGENS; BASIC BIOLOGICAL SCIENCES; Crystallography, X-Ray; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - metabolism; HISTOCOMPATIBILITY COMPLEX; HLA Antigens - chemistry; HLA Antigens - metabolism; HLA-G Antigens; human leukocyte antigen G, HLA-G; Humans; IMMUNITY; innate immunity; LEUKOCYTES; Models, Molecular; PEPTIDES; Protein Binding; Protein Conformation; Protein Stability; Protein Structure, Quaternary; STABILITY; structural immunology; Temperature
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2010.01.052

The highly polymorphic major histocompatibility complex class Ia (MHC-Ia) molecules present a broad array of peptides to the clonotypically diverse αβ T-cell receptors. In contrast, MHC-Ib molecules exhibit limited polymorphism and bind a more restricted peptide repertoire, in keeping with their major role in innate immunity. Nevertheless, some MHC-Ib molecules do play a role in adaptive immunity. While human leukocyte antigen E (HLA-E), the MHC-Ib molecule, binds a very restricted repertoire of peptides, the peptide binding preferences of HLA-G, the class Ib molecule, are less stringent, although the basis by which HLA-G can bind various peptides is unclear. To investigate how HLA-G can accommodate different peptides, we compared the structure of HLA-G bound to three naturally abundant self-peptides (RIIPRHLQL, KGPPAALTL and KLPQAFYIL) and their thermal stabilities. The conformation of HLA-GKGPPAALTL was very similar to that of the HLA-GRIIPRHLQL structure. However, the structure of HLA-GKLPQAFYIL not only differed in the conformation of the bound peptide but also caused a small shift in the α2 helix of HLA-G. Furthermore, the relative stability of HLA-G was observed to be dependent on the nature of the bound peptide. These peptide-dependent effects on the substructure of the monomorphic HLA-G are likely to impact on its recognition by receptors of both innate and adaptive immune systems.