A human β-III-spectrin spinocerebellar ataxia type 5 mutation causes high-affinity F-actin binding

Scientific Reports
Adam W AveryThomas S Hays

Abstract

Spinocerebellar ataxia type 5 (SCA5) is a human neurodegenerative disease that stems from mutations in the SPTBN2 gene encoding the protein β-III-spectrin. Here we investigated the molecular consequence of a SCA5 missense mutation that results in a L253P substitution in the actin-binding domain (ABD) of β-III-spectrin. We report that the L253P substitution in the isolated β-III-spectrin ABD causes strikingly high F-actin binding affinity (Kd = 75.5 nM) compared to the weak F-actin binding affinity of the wild-type ABD (Kd = 75.8 μM). The mutation also causes decreased thermal stability (Tm = 44.6 °C vs 59.5 °C). Structural analyses indicate that leucine 253 is in a loop at the interface of the tandem calponin homology (CH) domains comprising the ABD. Leucine 253 is predicted to form hydrophobic contacts that bridge the CH domains. The decreased stability of the mutant indicates that these bridging interactions are probably disrupted, suggesting that the high F-actin binding affinity of the mutant is due to opening of the CH domain interface. These results support a fundamental role for leucine 253 in regulating opening of the CH domain interface and binding of the ABD to F-actin. This study indicates that high-affinity actin bi...Continue Reading

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Citations

Feb 9, 2020·Cells·Diana C Muñoz-LassoPilar Gonzalez-Cabo
Jul 16, 2020·Acta Neuropathologica·Ben ReadheadMichelle E Ehrlich
Oct 29, 2017·Proceedings of the National Academy of Sciences of the United States of America·Adam W AveryThomas S Hays
Jul 17, 2018·Biophysical Journal·Michael E FealeyDavid D Thomas
Apr 4, 2021·International Journal of Molecular Sciences·Paula SanchoSergio Aguilera-Albesa
Apr 12, 2021·The Journal of Biological Chemistry·Robyn T RebbeckAdam W Avery

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Methods Mentioned

BETA
fluorescence complementation assay
FRET
PCR
gel filtration

Software Mentioned

Tasser
Image Studio Lite
Prism
PyMOL
Discovery Studio
GraphPad

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