期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-017-01367-w
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资金
- NIH [GM44757, AG32961, GM81303]
- NSF [MCB-1616854]
- NIH grant [GM44757, G20-RR31199]
- NIH training grant [T32 AR007612]
- School of Medicine
Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the cytoskeletal protein beta-III-spectrin. Previously, a SCA5 mutation resulting in a leucine-toproline 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 angstrom 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 alpha-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 beta-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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