3FON

Crystal structure of the Class I MHC Molecule H-2Kwm7 with a Single Self Peptide VNDIFEAI

Summary for 3FON

• Entry DOI: 10.2210/pdb3fon/pdb
• Related: 3FOL 3FOM
• Descriptor: MHC, Beta-2-microglobulin, Peptide, ... (4 entities in total)
• Functional Keywords: class i mhc, peptide complex, diabetes-protective effect, immune response, immunoglobulin domain, mhc i, secreted, immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 6
• Total formula weight: 88485.32

Authors

Malashkevich, V.N.,Qian, J.,Jarchum, I.,Yamada, T.,Mikesh, L.,Palmieri, E.,Lund, T.,Hattori, M.,Shabanowitz, J.,Hunt, D.F.,Ramagopal, U.A.,Brims, D.R.,Almo, S.C.,Nathenson, S.G.,DiLorenzo, T.P. (deposition date: 2008-12-30, release date: 2010-01-12, Last modification date: 2024-11-06)

Primary citation

Brims, D.R.,Qian, J.,Jarchum, I.,Mikesh, L.,Palmieri, E.,Ramagopal, U.A.,Malashkevich, V.N.,Chaparro, R.J.,Lund, T.,Hattori, M.,Shabanowitz, J.,Hunt, D.F.,Nathenson, S.G.,Almo, S.C.,Dilorenzo, T.P.
Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect.
Int.Immunol., 22:191-203, 2010

PubMed Abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic beta cells. In both humans and the non-obese diabetic (NOD) mouse model of T1D, class II MHC alleles are the primary determinant of disease susceptibility. However, class I MHC genes also influence risk. These findings are consistent with the requirement for both CD4(+) and CD8(+) T cells in the pathogenesis of T1D. Although a large body of work has permitted the identification of multiple mechanisms to explain the diabetes-protective effect of particular class II MHC alleles, studies examining the protective influence of class I alleles are lacking. Here, we explored this question by performing biochemical and structural analyses of the murine class I MHC molecule H-2K(wm7), which exerts a diabetes-protective effect in NOD mice. We have found that H-2K(wm7) molecules are predominantly occupied by the single self-peptide VNDIFERI, derived from the ubiquitous protein histone H2B. This unexpected finding suggests that the inability of H-2K(wm7) to support T1D development could be due, at least in part, to the failure of peptides from critical beta-cell antigens to adequately compete for binding and be presented to T cells. Predominant presentation of a single peptide would also be expected to influence T-cell selection, potentially leading to a reduced ability to select a diabetogenic CD8(+) T-cell repertoire. The report that one of the predominant peptides bound by T1D-protective HLA-A*31 is histone derived suggests the potential translation of our findings to human diabetes-protective class I MHC molecules.

PubMed: 20093428
DOI: 10.1093/intimm/dxp127

Experimental method

X-RAY DIFFRACTION (2.03 Å)