Model for the Peptide-free Conformation of Class II MHC Proteins

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2008 Jun 12

PMID 18545669

Citations 40

Authors

Corrie A Painter

Anthony Cruz

Gustavo E Lopez

Lawrence J Stern

Zarixia Zavala-Ruiz

Affiliations

Soon will be listed here.

Abstract

Background: Major histocompatibility complex proteins are believed to undergo significant conformational changes concomitant with peptide binding, but structural characterization of these changes has remained elusive.

Methodology/principal Findings: Here we use molecular dynamics simulations and experimental probes of protein conformation to investigate the peptide-free state of class II MHC proteins. Upon computational removal of the bound peptide from HLA-DR1-peptide complex, the alpha50-59 region folded into the P1-P4 region of the peptide binding site, adopting the same conformation as a bound peptide. Strikingly, the structure of the hydrophobic P1 pocket is maintained by engagement of the side chain of Phe alpha54. In addition, conserved hydrogen bonds observed in crystal structures between the peptide backbone and numerous MHC side chains are maintained between the alpha51-55 region and the rest of the molecule. The model for the peptide-free conformation was evaluated using conformationally-sensitive antibody and superantigen probes predicted to show no change, moderate change, or dramatic changes in their interaction with peptide-free DR1 and peptide-loaded DR1. The binding observed for these probes is in agreement with the movements predicted by the model.

Conclusion/significance: This work presents a molecular model for peptide-free class II MHC proteins that can help to interpret the conformational changes known to occur within the protein during peptide binding and release, and can provide insight into possible mechanisms for DM action.

Citing Articles

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Dynamically Driven Allostery in MHC Proteins: Peptide-Dependent Tuning of Class I MHC Global Flexibility.

Ayres C, Abualrous E, Bailey A, Abraham C, Hellman L, Corcelli S Front Immunol. 2019; 10:966.

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