幽灵蛋白
肌动蛋白
错义突变
突变
结合位点
肌动蛋白结合蛋白
血浆蛋白结合
细胞骨架
绑定域
生物
生物物理学
细胞生物学
化学
肌动蛋白细胞骨架
生物化学
细胞
基因
作者
Adam W. Avery,Michael E. Fealey,Fengbin Wang,Albina Orlova,Andrew R. Thompson,David D. Thomas,Thomas S. Hays,Edward H. Egelman
标识
DOI:10.1038/s41467-017-01367-w
摘要
Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the cytoskeletal protein β-III-spectrin. Previously, a SCA5 mutation resulting in a leucine-to-proline substitution (L253P) in the actin-binding domain (ABD) was shown to cause a 1000-fold increase in actin-binding affinity. However, the structural basis for this increase is unknown. Here, we report a 6.9 Å cryo-EM structure of F-actin complexed with the L253P ABD. This structure, along with co-sedimentation and pulsed-EPR measurements, demonstrates that high-affinity binding caused by the CH2-localized mutation is due to opening of the two CH domains. This enables CH1 to bind actin aided by an unstructured N-terminal region that becomes α-helical upon binding. This helix is required for association with actin as truncation eliminates binding. Collectively, these results shed light on the mechanism by which β-III-spectrin, and likely similar actin-binding proteins, interact with actin, and how this mechanism can be perturbed to cause disease.
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