Structural analysis of H2-D^b class I molecules containing two different allelic forms of the type 1 diabetes susceptibility factor beta-2 microglobulin: Implications for the mechanism under

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• 作者：Matthew M. Roden ; Daniel R. Brims ; Alexander A. Fedorov ; Teresa P. DiLorenzo ; Steven C. Almo and Stanley G. Nathenson
• 关键词：Type 1a diabetes ; Major histocompatibility complex class I molecules (MHC-I) ; Beta-2 microglobulin (β ; 2m) ; Nonobese diabetic mice (NOD)
• 刊名：Molecular Immunology
• 出版年：2006
• 出版时间：March 2006
• 年：2006
• 卷：43
• 期：9
• 页码：1370-1378
• 全文大小：457 K

文摘

Beta-2 microglobulin (β2m) is a member of the immunoglobulin-like domain superfamily that is an essential structural subunit of the MHC class I (MHC-I) molecule. β2m was previously identified as a susceptibility factor for the development of type 1 diabetes (T1D) in NOD mice, whereby transgenic expression of the β2m^a variant, but not the β2m^b variant, restored diabetes susceptibility to normally resistant NOD.β2m^null mice. Here we report the crystal structures and thermodynamic stabilities of the NOD MHC-I molecule H2-D^b containing these two variants. Our results reveal subtle differences in the structures of the β2m variants, namely in minor loop shifts and in variations in the hydrogen bonding networks at the interfaces between the components of the ternary complex. We also demonstrate that the thermodynamic stabilities of the β2m variants in isolation differ. However, the conformation of the peptide in the MHC cleft is unchanged in β2m allelic D^b complexes, as are the TCR recognition surfaces. Thus, despite modest structural differences between allelic complexes, the evidence indicates that D^b peptide presentation of the representative peptide is unchanged in the context of either β2m allelic variant. These data suggest that other mechanisms, such as differential association of MHC-I in multiprotein complexes, are likely responsible for the effect of β2m on T1D development.