TY - JOUR
T1 - Structural analysis of H2-Db class I molecules containing two different allelic forms of the type 1 diabetes susceptibility factor beta-2 microglobulin
T2 - Implications for the mechanism underlying variations in antigen presentation
AU - Roden, Matthew M.
AU - Brims, Daniel R.
AU - Fedorov, Alexander A.
AU - DiLorenzo, Teresa P.
AU - Almo, Steven C.
AU - Nathenson, Stanley G.
N1 - Funding Information:
We thank the Albert Einstein Center for Synchrotron Biosciences for providing beamtime at the NSLS in Brookhaven National Laboratories. Special thanks to Dr. Matthew Scharff for critical review of the manuscript. This work was supported by National Institutes of Health grants DK65247 (S.G.N., S.C.A. and T.P.D.), AI07289 (S.G.N.), DK64315 (T.P.D.), DK52956 (T.P.D), and DK20541 (Albert Einstein College of Medicine's Diabetes Research and Training Center). M.M.R. was supported by National Institutes of Health Training Grants T32GM07491 and T32CA9173. D.R.B. is supported by T32CA9173.
PY - 2006/3
Y1 - 2006/3
N2 - 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 β2ma variant, but not the β2mb variant, restored diabetes susceptibility to normally resistant NOD.β2mnull mice. Here we report the crystal structures and thermodynamic stabilities of the NOD MHC-I molecule H2-Db 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 Db complexes, as are the TCR recognition surfaces. Thus, despite modest structural differences between allelic complexes, the evidence indicates that Db 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.
AB - 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 β2ma variant, but not the β2mb variant, restored diabetes susceptibility to normally resistant NOD.β2mnull mice. Here we report the crystal structures and thermodynamic stabilities of the NOD MHC-I molecule H2-Db 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 Db complexes, as are the TCR recognition surfaces. Thus, despite modest structural differences between allelic complexes, the evidence indicates that Db 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.
KW - Beta-2 microglobulin (β2m)
KW - Major histocompatibility complex class I molecules (MHC-I)
KW - Nonobese diabetic mice (NOD)
KW - Type 1a diabetes
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U2 - 10.1016/j.molimm.2005.08.005
DO - 10.1016/j.molimm.2005.08.005
M3 - Article
C2 - 16229893
AN - SCOPUS:33644822545
SN - 0161-5890
VL - 43
SP - 1370
EP - 1378
JO - Molecular Immunology
JF - Molecular Immunology
IS - 9
ER -