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Atomistic structure and dynamics of the human MHC-I peptide-loading complex
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Atomistic structure and dynamics of the human MHC-I peptide-loading complex
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Atomistic structure and dynamics of the human MHC-I peptide-loading complex
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Journal Article
Atomistic structure and dynamics of the human MHC-I peptide-loading complex
2020
Overview
The major histocompatibility complex class-I (MHC-I) peptideloading complex (PLC) is a cornerstone of the human adaptive immune system, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells. Based on a recent low-resolution cryo-electron microscopy (cryo-EM) structure of this large membrane-bound protein complex, we report an atomistic model of the PLC and study its conformational dynamics on the multimicrosecond time scale using all-atom molecular dynamics (MD) simulations in an explicit lipid bilayer and water environment (1.6 million atoms in total). The PLC has a layered structure, with two editing modules forming a flexible protein belt surrounding a stable, catalytically active core. Tapasin plays a central role in the PLC, stabilizing the MHC-I binding groove in a conformation reminiscent of antigen-loaded MHC-I. The MHC-I–linked glycan steers a tapasin loop involved in peptide editing toward the binding groove. Tapasin conformational dynamics are also affected by calreticulin through a conformational selection mechanism that facilitates MHC-I recruitment into the complex.
Publisher
National Academy of Sciences
Subject
/ Antigens
/ Binding
/ Biophysics and Computational Biology
/ Editing
/ Glycan
/ Grooves
/ Histocompatibility Antigens Class I - metabolism
/ Histocompatibility Antigens Class I - ultrastructure
/ Humans
/ Lipids
/ Major histocompatibility complex
/ Membrane Transport Proteins - metabolism
/ Membrane Transport Proteins - ultrastructure
/ Molecular Dynamics Simulation
/ Peptides
/ Polysaccharides - metabolism
/ Protein Disulfide-Isomerases - metabolism
/ Proteins
/ Tapasin
