Structural basis for high-affinity actin binding revealed by a β-III-spectrin SCA5 missense mutation

Adam W. Avery, Michael E. Fealey, Fengbin Wang, Albina Orlova, Andrew R. Thompson, David D. Thomas, Thomas S. Hays () and Edward H. Egelman
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Adam W. Avery: University of Minnesota
Michael E. Fealey: University of Minnesota
Fengbin Wang: University of Virginia
Albina Orlova: University of Virginia
Andrew R. Thompson: University of Minnesota
David D. Thomas: University of Minnesota
Thomas S. Hays: University of Minnesota
Edward H. Egelman: University of Virginia

Nature Communications, 2017, vol. 8, issue 1, 1-7

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01367-w

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