ArticleScientific reports2016
A human β-III-spectrin spinocerebellar ataxia type 5 mutation causes high-affinity F-actin binding.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 37 citations in OpenAlex.
- Impaired motor activity in a CRISPR SCA5 L253P knock-in mouse is associated with selective β-III-spectrin subcellular redistribution in the cerebellum.bioRxiv : the preprint server for biology · 2026Article
- Paralemmin-1 controls the nanoarchitecture of the neuronal submembrane cytoskeleton.Science advances · 2025Article
- Molecular consequences of SCA5 mutations in the spectrin-repeat domains of β-III-spectrin.bioRxiv : the preprint server for biology · 2024Article
- Multi-omics pan-cancer study of SPTBN2 and its value as a potential therapeutic target in pancreatic cancer.Scientific reports · 2024Article
- Structural Dynamics of Protein Interactions Using Site-Directed Spin Labeling of Cysteines to Measure Distances and Rotational Dynamics with EPR Spectroscopy.Applied magnetic resonance · 2024Article
- Cardiomyopathy-associated variants alter the structure and function of the α-actinin-2 actin-binding domain.Biochemical and biophysical research communications · 2023Article
- Increased Actin Binding Is a Shared Molecular Consequence of Numerous SCA5 Mutations in β-III-Spectrin.Cells · 2023Article
- Competition between myosin II and βeLife · 2023Article
- Increased actin binding is a shared molecular consequence of numerous spinocerebellar ataxia mutations in β-III-spectrin.bioRxiv : the preprint server for biology · 2023Article
- Spectrins: molecular organizers and targets of neurological disorders.Nature reviews. Neuroscience · 2023Review
- β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity.Scientific reports · 2022Article
- Expanding the β-III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration.International journal of molecular sciences · 2021Article
- Article
- miR155 regulation of behavior, neuropathology, and cortical transcriptomics in Alzheimer's disease.Acta neuropathologica · 2020Article
- Article
- Review
- Dynamics of Dystrophin's Actin-Binding Domain.Biophysical journal · 2018Article
- Structural basis for high-affinity actin binding revealed by a β-III-spectrin SCA5 missense mutation.Nature communications · 2017Article
- β-III-spectrin spinocerebellar ataxia type 5 mutation reveals a dominant cytoskeletal mechanism that underlies dendritic arborization.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Novel drug discovery platform for spinocerebellar ataxia, using fluorescence technology targeting β-III-spectrin.The Journal of biological chemistryArticle
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Authors and funding
4 authors at 1 institution in 1 country.
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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 binding of L253P β-III-spectrin is a likely driver of neurodegeneration.
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