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Conformational variation in structures of classical and non-classical MHCII proteins and functional implications.

ABSTRACT: Recent structural characterizations of classical and non-classical major histocompatibility complex class II (MHCII) proteins have provided a view into the dynamic nature of the MHCII-peptide binding groove and the role that structural changes play in peptide loading processes. Although there have been numerous reports of crystal structures for MHCII-peptide complexes, a detailed analysis comparing all the structures has not been reported, and subtle conformational variations present in these structures may not have been fully appreciated. We compared the 91 MHCII crystal structures reported in the PDB to date, including an HLA-DR mutant particularly susceptible to DM-mediated peptide exchange, and reviewed experimental and computational studies of the effect of peptide binding on MHCII structure. These studies provide evidence for conformational lability in and around the ?-subunit 3-10 helix at residues ?48-51, a region known to be critical for HLA-DM-mediated peptide exchange. A biophysical study of MHC-peptide hydrogen bond strengths and a recent structure of the non-classical MHCII protein HLA-DO reveal changes in the same region. Conformational variability was observed also in the vicinity of a kink in the ?-subunit helical region near residue ?66 and in the orientation and loop conformation in the ?2 Ig domain. Here, we provide an overview of the regions within classical and non-classical MHCII proteins that display conformational changes and the potential role that these changes may have in the peptide loading/exchange process.

SUBMITTER: Painter CA

PROVIDER: S-EPMC3471379 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Conformational variation in structures of classical and non-classical MHCII proteins and functional implications.

Painter Corrie A CA Stern Lawrence J LJ

Immunological reviews 20121101 1

Recent structural characterizations of classical and non-classical major histocompatibility complex class II (MHCII) proteins have provided a view into the dynamic nature of the MHCII-peptide binding groove and the role that structural changes play in peptide loading processes. Although there have been numerous reports of crystal structures for MHCII-peptide complexes, a detailed analysis comparing all the structures has not been reported, and subtle conformational variations present in these st ...[more]

PMID: 23046127

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Project description:Protein crystallography data collection at synchrotrons is routinely carried out at cryogenic temperatures to mitigate radiation damage. Although damage still takes place at 100?K and below, the immobilization of free radicals increases the lifetime of the crystals by approximately 100-fold. Recent studies have shown that flash-cooling decreases the heterogeneity of the conformational ensemble and can hide important functional mechanisms from observation. These discoveries have motivated increasing numbers of experiments to be carried out at room temperature. However, the trade-offs between increased risk of radiation damage and increased observation of alternative conformations at room temperature relative to cryogenic temperature have not been examined. A considerable amount of effort has previously been spent studying radiation damage at cryo-temperatures, but the relevance of these studies to room temperature diffraction is not well understood. Here, the effects of radiation damage on the conformational landscapes of three different proteins (T. danielli thaumatin, hen egg-white lysozyme and human cyclophilin A) at room (278?K) and cryogenic (100?K) temperatures are investigated. Increasingly damaged datasets were collected at each temperature, up to a maximum dose of the order of 107?Gy at 100?K and 105?Gy at 278?K. Although it was not possible to discern a clear trend between damage and multiple conformations at either temperature, it was observed that disorder, monitored by B-factor-dependent crystallographic order parameters, increased with higher absorbed dose for the three proteins at 100?K. At 278?K, however, the total increase in this disorder was only statistically significant for thaumatin. A correlation between specific radiation damage affecting side chains and the amount of disorder was not observed. This analysis suggests that elevated conformational heterogeneity in crystal structures at room temperature is observed despite radiation damage, and not as a result thereof.

Dataset Information

Conformational variation in structures of classical and non-classical MHCII proteins and functional implications.

Publications

Conformational variation in structures of classical and non-classical MHCII proteins and functional implications.

Similar Datasets

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