Structural analysis of H2-Db class I molecules containing two different allelic forms of the type 1 diabetes susceptibility factor beta-2 microglobulin

Implications for the mechanism underlying variations in antigen presentation

Matthew M. Roden, Daniel R. Brims, Alexander A. Fedorov, Teresa P. DiLorenzo, Steven C. Almo, Stanley G. Nathenson

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1370-1378
Number of pages9
JournalMolecular Immunology
Volume43
Issue number9
DOIs
StatePublished - Mar 2006

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beta 2-Microglobulin
Antigen Presentation
Type 1 Diabetes Mellitus
Thermodynamics
Peptides
Multiprotein Complexes
Inbred NOD Mouse
Hydrogen Bonding

Keywords

  • Beta-2 microglobulin (β2m)
  • Major histocompatibility complex class I molecules (MHC-I)
  • Nonobese diabetic mice (NOD)
  • Type 1a diabetes

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology

Cite this

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title = "Structural analysis of H2-Db class I molecules containing two different allelic forms of the type 1 diabetes susceptibility factor beta-2 microglobulin: Implications for the mechanism underlying variations in antigen presentation",
abstract = "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.",
keywords = "Beta-2 microglobulin (β2m), Major histocompatibility complex class I molecules (MHC-I), Nonobese diabetic mice (NOD), Type 1a diabetes",
author = "Roden, {Matthew M.} and Brims, {Daniel R.} and Fedorov, {Alexander A.} and DiLorenzo, {Teresa P.} and Almo, {Steven C.} and Nathenson, {Stanley G.}",
year = "2006",
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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.

PY - 2006/3

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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.

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