Atomistic structure and dynamics of the human MHC-I peptide-loading complex.
Olivier FisetteGunnar F SchröderLars V SchäferPublished in: Proceedings of the National Academy of Sciences of the United States of America (2020)
The major histocompatibility complex class-I (MHC-I) peptide-loading 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.
Keyphrases
- molecular dynamics
- molecular dynamics simulations
- density functional theory
- endothelial cells
- crispr cas
- electron microscopy
- single molecule
- binding protein
- drug delivery
- induced apoptosis
- cell proliferation
- oxidative stress
- dna binding
- pluripotent stem cells
- fatty acid
- dendritic cells
- transcription factor
- cancer therapy
- small molecule
- mass spectrometry
- protein protein
- network analysis
- cell cycle arrest
- transition metal