Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093, United States.
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
Biochemistry. 2023 Nov 7;62(21):3036-3040. doi: 10.1021/acs.biochem.3c00349. Epub 2023 Oct 3.
Human annexin A7, a calcium- and phospholipid-binding protein, governs calcium homeostasis, plasma membrane repair, apoptosis, and tumor progression. A7 contains an N-terminal proline-rich domain (PRD; 180 residues, ∼24% prolines) that determines its functional specificity. Using microscopy and dye-binding assays, we show that recombinant A7 and its isolated PRD spontaneously phase separate into spherical condensates, which subsequently transform into β-sheet-rich fibrils. We demonstrate that fibrillization of A7-PRD proceeds via primary nucleation and fibril-catalyzed secondary nucleation processes, as determined by chemical kinetics, providing a mechanistic basis for its amyloid assembly. This study confirms and highlights a subclass of eukaryotic PRDs prone to forming aggregates with important physiological and pathological implications.
人膜联蛋白 A7 是一种钙和磷脂结合蛋白，可调节钙稳态、质膜修复、细胞凋亡和肿瘤进展。A7 含有一个 N 端富含脯氨酸的结构域（PRD；180 个残基，约 24%脯氨酸），决定了其功能的特异性。通过显微镜和染料结合实验，我们发现重组 A7 和其分离的 PRD 可自发相分离成球形凝聚物，随后转化为富含β-折叠的纤维。我们通过化学动力学证明，A7-PRD 的纤维形成经历了初级成核和纤维催化的二级成核过程，为其淀粉样蛋白组装提供了机制基础。本研究证实并强调了一类易形成具有重要生理和病理意义的聚集物的真核 PRD 亚类。
