Department of Bioengineering, Recep Tayyip Erdogan University, Faculty of Engineering, Fener, Rize, Turkey.
Department of Bioengineering, Marmara University, Faculty of Engineering, Goztepe, Istanbul, Turkey.
PLoS One. 2020 May 18;15(5):e0232849. doi: 10.1371/journal.pone.0232849. eCollection 2020.
Class I Major Histocompatibility Complex (MHC) binds short antigenic peptides with the help of Peptide Loading Complex (PLC), and presents them to T-cell Receptors (TCRs) of cytotoxic T-cells and Killer-cell Immunglobulin-like Receptors (KIRs) of Natural Killer (NK) cells. With more than 10000 alleles, human MHC (Human Leukocyte Antigen, HLA) is the most polymorphic protein in humans. This allelic diversity provides a wide coverage of peptide sequence space, yet does not affect the three-dimensional structure of the complex. Moreover, TCRs mostly interact with HLA in a common diagonal binding mode, and KIR-HLA interaction is allele-dependent. With the aim of establishing a framework for understanding the relationships between polymorphism (sequence), structure (conserved fold) and function (protein interactions) of the human MHC, we performed here a local frustration analysis on pMHC homology models covering 1436 HLA I alleles. An analysis of local frustration profiles indicated that (1) variations in MHC fold are unlikely due to minimally-frustrated and relatively conserved residues within the HLA peptide-binding groove, (2) high frustration patches on HLA helices are either involved in or near interaction sites of MHC with the TCR, KIR, or tapasin of the PLC, and (3) peptide ligands mainly stabilize the F-pocket of HLA binding groove.
I 类主要组织相容性复合体 (MHC) 在肽装载复合物 (PLC) 的帮助下结合短抗原肽，并将其呈递给细胞毒性 T 细胞的 T 细胞受体 (TCR) 和自然杀伤 (NK) 细胞的杀伤细胞免疫球蛋白样受体 (KIR)。人类 MHC（人类白细胞抗原，HLA）拥有超过 10000 个等位基因，是人类中最多态性的蛋白质。这种等位基因多样性提供了广泛的肽序列空间覆盖，但不会影响复合物的三维结构。此外，TCR 主要以常见的对角结合模式与 HLA 相互作用，而 KIR-HLA 相互作用则依赖于等位基因。为了建立理解人类 MHC 多态性（序列）、结构（保守折叠）和功能（蛋白相互作用）之间关系的框架，我们在此对涵盖 1436 个 HLA I 等位基因的 pMHC 同源模型进行了局部受挫分析。局部受挫分析表明：(1) HLA 肽结合槽内最小受挫且相对保守的残基不太可能导致 MHC 折叠发生变化；(2) HLA 螺旋上的高受挫斑块要么涉及 MHC 与 TCR、KIR 或 PLC 的 tapasin 的相互作用位点，要么位于其附近；(3) 肽配体主要稳定 HLA 结合槽的 F 口袋。
