School of Science, Jacobs University Bremen, Bremen, Germany.
Physik-Department, T38, Technical University of Munich, Munich, Germany.
Protein Sci. 2022 Dec;31(12):e4478. doi: 10.1002/pro.4478.
The cell biology and biochemistry of peptide exchange on major histocompatibility complex class I (MHC-I) proteins are of great interest in the study of immunodominance, which requires iterative optimization of peptide affinity, and cross-presentation of pathogen and tumor antigens, in which endogenous peptides are exchanged for exogenous ones. Even though several methods exist to catalyze peptide exchange on recombinant MHC-I proteins, the cellular conditions and mechanisms allowing for peptide exchange in vivo remain unclear. Here, we demonstrate that low pH, as present in endosomes, indeed triggers peptide exchange, and we dissect the individual steps of the exchange reaction. We find that low pH stabilizes the peptide-empty forms of MHC-I that occur as intermediates of the exchange reaction, and that is synergizes with dipeptides and with disulfide-mediated stabilization of MHC-I.
主要组织相容性复合体 I 类（MHC-I）蛋白上肽交换的细胞生物学和生物化学在免疫优势研究中非常重要，这需要对肽亲和力进行反复优化，以及对外源肽进行交叉呈递，以交换内源性肽。尽管存在几种方法可以催化重组 MHC-I 蛋白上的肽交换，但允许体内肽交换的细胞条件和机制仍不清楚。在这里，我们证明了内体中存在的低 pH 值确实会触发肽交换，并解析了交换反应的各个步骤。我们发现低 pH 值稳定了作为交换反应中间产物的肽空形式的 MHC-I，并且与二肽和 MHC-I 的二硫键介导的稳定协同作用。
