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

Author

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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)

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.

Suggested Citation

  • Adam W. Avery & Michael E. Fealey & Fengbin Wang & Albina Orlova & Andrew R. Thompson & David D. Thomas & Thomas S. Hays & Edward H. Egelman, 2017. "Structural basis for high-affinity actin binding revealed by a β-III-spectrin SCA5 missense mutation," Nature Communications, Nature, vol. 8(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01367-w
    DOI: 10.1038/s41467-017-01367-w
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