Institute of Protein Biochemistry, Ulm University, Ulm, Germany.
Institute of Physics, University of Augsburg, Augsburg, Germany.
Nat Commun. 2024 Nov 7;15(1):9648. doi: 10.1038/s41467-024-54091-7.
Systemic ALys amyloidosis is a debilitating protein misfolding disease that arises from the formation of amyloid fibrils from C-type lysozyme. We here present a 2.8 Å cryo-electron microscopy structure of an amyloid fibril, which was isolated from the abdominal fat tissue of a patient who expressed the D87G variant of human lysozyme. We find that the fibril possesses a stable core that is formed by all 130 residues of the fibril precursor protein. There are four disulfide bonds in each fibril protein that connect the same residues as in the globularly folded protein. As the conformation of lysozyme in the fibril is otherwise fundamentally different from native lysozyme, our data provide a structural rationale for the need of protein unfolding in the development of systemic ALys amyloidosis.
系统性 AL 淀粉样变是一种使人虚弱的蛋白质错误折叠疾病，源于 C 型溶菌酶形成淀粉样纤维。我们在此展示了源自一位表达人溶菌酶 D87G 变体的患者腹部脂肪组织的淀粉样纤维的 2.8Å 冷冻电镜结构。我们发现纤维具有由纤维前体蛋白的所有 130 个残基形成的稳定核心。每个纤维蛋白中有四个二硫键，将球状折叠蛋白中的相同残基连接起来。由于纤维中溶菌酶的构象与天然溶菌酶根本不同，因此我们的数据为系统性 AL 淀粉样变发展中需要蛋白质展开提供了结构基础。
