Antigen presentation by MHC-II is shaped by competitive and cooperative allosteric mechanisms of peptide exchange

被引:0
|
作者
Guenther, Matthias [1 ]
Sticht, Jana [2 ]
Freund, Christian [2 ]
Hoefer, Thomas [1 ]
机构
[1] German Canc Res Ctr, Div Theoret Syst Biol, D-69120 Heidelberg, Germany
[2] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany
关键词
HLA-DM; MOLECULES; PROTEINS; DYNAMICS; BINDING;
D O I
10.1016/j.str.2024.11.014
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Major histocompatibility complex class II (MHC-II) presents antigens to T helper cells. The spectrum of presented peptides is regulated by the exchange catalyst human leukocyte antigen DM (HLA-DM), which dissociates peptide-MHC-II complexes in the endosome. How susceptible a peptide is to HLA-DM is mechanistically not understood. Here, we present a data-driven mathematical model for the conformational landscape of MHC-II that explains the wide range of measured HLA-DM susceptibilities and predicts why some peptides are largely HLA-DM-resistant. We find that the conformational plasticity of MHC-II mediates both allosteric competition and cooperation between peptide and HLA-DM. Competition causes HLA-DM susceptibility to be proportional to the intrinsic peptide off-rate. Remarkably, diverse MHC-II allotypes with conserved HLA-DM interactions show a universal linear susceptibility function. However, HLA-DM-resistant peptides deviate from this susceptibility function; we predict resistance to be caused by fast peptide association with MHC-II. Thus, our study provides quantitative insight into peptide and MHC-II allotype parameters that shape class-II antigen presentation.
引用
收藏
页数:26
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