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Structural basis for high-affinity actin binding revealed by a β-III-spectrin SCA5 missense mutation
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Structural basis for high-affinity actin binding revealed by a β-III-spectrin SCA5 missense mutation
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Structural basis for high-affinity actin binding revealed by a β-III-spectrin SCA5 missense mutation
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Journal Article
Structural basis for high-affinity actin binding revealed by a β-III-spectrin SCA5 missense mutation
2017
Overview
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.
The disease causing L253P mutation in the actin-binding domain (ABD) of β-III-spectrin drastically increases actin-binding affinity. Here, the authors present the cryo-EM structure of F-actin complexed with the ABD mutant and double electron–electron resonance measurements show how the mutation affects the ABD conformational state.
