Antigenic Peptide Loading into Major Histocompatibility Complex Class I Is Driven by the Substrate N-Terminus
作者机构：Key Laboratory of System Biomedicine(Ministry of Education)Shanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghai 200240 Bio-X InstitutesKey Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersShanghai Jiao Tong UniversityShanghai 200030
出 版 物：《CCS Chemistry》 (中国化学会会刊（英文）)
年 卷 期：2022年第4卷第3期
页 面：910-925页
学科分类：07[理学] 070303[理学-有机化学] 0703[理学-化学]
基 金：The authors acknowledge the Natural Science Foundation of Shanghai(nos.20511101900 20ZR1427200 and 20ZR1425400).
主 题：antigenic peptide MHC-I molecule loading molecular dynamics simulations Markov state model
摘 要：Major histocompatibility complex class I(MHC-I),a key element of the acquired immune system,plays essential roles in activating CD8^(+)T cells by recognizing intracellular antigens derived from pathogens and cancer.Assembly of MHC-I and antigen peptides is critical for the antigen presentation on the cell surface.However,the structural dynamics of antigenic peptide loading into MHC-I,at atomistic resolution,is still elusive.Here,by constructing a Markov state model(MSM)based onlarge scale all-atommolecular dynamics(MDs)simulations with an aggregated simulation time∼24μs,we reveal the detailed molecular mechanism underlying the peptide-loading dynamics into MHC-I and identify the key intermediates with associated thermodynamic/kinetic properties.Furthermore,we examine how the chaperone tapasin-binding protein related(TAPBPR)participates in promoting the peptide loading,and the results show that TAPBPR,by binding to the F pocket,allosterically modulates the structures of the distant pocket B,resulting in formation of a peptide-receptive conformation ideal for accommodating the incoming peptide N-terminus.This study provides fundamental structural insights for the peptide loading into MHC-I in both chaperone uncatalyzed and catalyzed contexts.
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