Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy
Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy
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DOI：
10.1038/s41467-019-11320-8
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发表时间：
2019-08-21
影响因子：
16.6
通讯作者：
Schroeder, Gunnar F.
中科院分区：
文献类型：
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作者：
Roeder, Christine;Vettore, Nicola;Schroeder, Gunnar F.
淀粉样蛋白原纤维的高分辨率结构信息对于理解其形成机制和在蛋白质错误折叠疾病的背景下合理设计淀粉样蛋白抑制剂是至关重要的。磷脂酰肌醇-3-激酶（PI 3 K-SH 3）的Src同源3结构域是淀粉样蛋白系统的模型，其在我们对蛋白质错误折叠和聚集的基本理解中起关键作用。在这里，我们提出了PI 3 K-SH 3淀粉样原纤维的原子模型，通过冷冻电子显微镜（cryo-EM）确定分辨率为3.4埃。原纤维是由两个相互缠绕的原丝，创造一个接口跨越13个残基，从每个单体。该模型包含总共86个氨基酸中的残基1-77，缺失的残基位于高度柔性的C-末端。原纤维结构使我们能够合理化的化学保守的点突变，以及先前报道的序列扰动对PI 3 K-SH 3原纤维的形成和生长的影响。
High resolution structural information on amyloid fibrils is crucial for the understanding of their formation mechanisms and for the rational design of amyloid inhibitors in the context of protein misfolding diseases. The Src-homology 3 domain of phosphatidyl-inositol-3-kinase (PI3K-SH3) is a model amyloid system that plays a pivotal role in our basic understanding of protein misfolding and aggregation. Here, we present the atomic model of the PI3K-SH3 amyloid fibril with a resolution determined to 3.4 angstrom by cryo-electron microscopy (cryo-EM). The fibril is composed of two intertwined protofilaments that create an interface spanning 13 residues from each monomer. The model comprises residues 1-77 out of 86 amino acids in total, with the missing residues located in the highly flexible C-terminus. The fibril structure allows us to rationalise the effects of chemically conservative point mutations as well as of the previously reported sequence perturbations on PI3K-SH3 fibril formation and growth.