Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
Biophys J. 2023 May 2;122(9):1665-1677. doi: 10.1016/j.bpj.2023.03.032. Epub 2023 Mar 24.
Major histocompatibility complex class II (MHC-II) plays an indispensable role in activating CD4 T cell immune responses by presenting antigenic peptides on the cell surface for recognition by T cell receptors. The assembly of MHC-II and antigenic peptide is therefore a prerequisite for the antigen presentation. To date, however, the atomic-level mechanism underlying the peptide-loading dynamics for MHC-II is still elusive. Here, by constructing Markov state models based on extensive all-atom molecular dynamics simulations, we reveal the complete peptide-loading dynamics into MHC-II for one SARS-CoV-2 S-protein-derived antigenic peptide (ITRFQTLLALHRSYL). Our Markov state model identifies six metastable states (S1-S6) during the peptide-loading process and determines two dominant loading pathways. The peptide could potentially approach the antigen-binding groove via either its N- or C-terminus. Then, the consecutive insertion of several anchor residues into the binding pockets profoundly dictates the peptide-loading dynamics. Notably, the MHC-II αA52-E55 motif could guide the peptide loading into the antigen-binding groove via forming β-sheets conformation with the incoming peptide. The rate-limiting step, namely S5→S6, is mainly attributed to a considerable desolvation penalty triggered by the binding of the peptide C-terminus. Moreover, we further examined the conformational changes associated with the peptide exchange process catalyzed by the chaperon protein HLA-DM. A flipped-out conformation of MHC-II αW43 captured in S1-S3 is considered a critical anchor point for HLA-DM to modulate the structural dynamics. Our work provides deep structural insights into the key regulatory factors in MHC-II responsible for peptide recognition and guides future design for peptide vaccines against SARS-CoV-2.
主要组织相容性复合体 II 类（MHC-II）在通过在细胞表面呈现抗原肽以供 T 细胞受体识别来激活 CD4 T 细胞免疫反应方面发挥着不可或缺的作用。因此，MHC-II 与抗原肽的组装是抗原呈递的前提。然而，迄今为止，MHC-II 中肽加载动力学的原子水平机制仍难以捉摸。在这里，我们通过基于广泛的全原子分子动力学模拟构建马尔可夫状态模型，揭示了 SARS-CoV-2 S 蛋白衍生的一种抗原肽（ITRFQTLLALHRSYL）进入 MHC-II 的完整肽加载动力学。我们的马尔可夫状态模型在肽加载过程中识别出六个亚稳态（S1-S6），并确定了两个主要的加载途径。肽有可能通过其 N 端或 C 端接近抗原结合槽。然后，几个锚定残基连续插入结合口袋深刻地决定了肽加载动力学。值得注意的是，MHC-II αA52-E55 基序可以通过与进入的肽形成β-折叠构象来指导肽加载进入抗原结合槽。限速步骤，即 S5→S6，主要归因于肽 C 端结合引起的相当大的去溶剂化惩罚。此外，我们进一步研究了伴随伴娘蛋白 HLA-DM 催化的肽交换过程的构象变化。在 S1-S3 中捕获的 MHC-II αW43 翻转构象被认为是 HLA-DM 调节结构动力学的关键锚定点。我们的工作深入了解了 MHC-II 中负责肽识别的关键调节因子，并为针对 SARS-CoV-2 的肽疫苗的未来设计提供了指导。
