TY  - JOUR
AU  - Fisette, Olivier
AU  - Schröder, Gunnar F.
AU  - Schäfer, Lars V.
TI  - Atomistic structure and dynamics of the human MHC-I peptide-loading complex
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 117
IS  - 34
SN  - 1091-6490
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - FZJ-2021-00347
SP  - 20597 - 20606
PY  - 2020
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 32788370
UR  - <Go to ISI:>//WOS:000572978200009
DO  - DOI:10.1073/pnas.2004445117
UR  - https://juser.fz-juelich.de/record/889726
ER  -