Antigenic Peptide Loading into Major Histocompatibility Complex Class I Is Driven by the Substrate N-Terminus  

作　　者：Mengna Lin Honglin Xu Yi Shi Lin-Tai Da 

机构地区：[1]Key Laboratory of System Biomedicine(Ministry of Education),Shanghai Center for Systems Biomedicine,Shanghai Jiao Tong University,Shanghai 200240 [2]Bio-X Institutes,Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders,Shanghai Jiao Tong University,Shanghai 200030

出　　处：《CCS Chemistry》2022年第3期910-925,共16页中国化学会会刊（英文）

基　　金：The authors acknowledge the Natural Science Foundation of Shanghai(nos.20511101900,20ZR1427200,and 20ZR1425400).

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.

关 键 词：antigenic peptide MHC-I molecule LOADING molecular dynamics simulations Markov state model 

分 类 号：O62[理学—有机化学]