Early-phase drug discovery of β-III-spectrin actin-binding modulators for treatment of spinocerebellar ataxia type 5

Guhathakurta, Piyali; Rebbeck, Robyn T.; Denha, Sarah A.; Keller, Amanda R.; Carter, Anna L.; Atang, Alexandra E.; Svensson, B. G.; Thomas, David D.; Hays, Thomas S.; Avery, Adam W.

doi:10.1016/j.jbc.2023.102956

Cited by 5 publications

(4 citation statements)

References 41 publications

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“…Based on the nearly identical impact of the T247M and M228T variants on the structure and function of the ABD, reported here, we expect M228T will show cause similar aggregation and loss of Z-disk incorporation as T247M. Drug-like small molecules have been identified that partially ameliorate high-affinity actin binding of a L253P mutant β-III-spectrin ABD [37]. Drug screening for α-actinin-2 may also identify actin-binding modulators useful in treatment in cardiomyopathy.…”

Section: Human α-Actinin-2 Cardiomyopathy Missense Variants Attain Fo...mentioning

confidence: 53%

Cardiomyopathy-associated variants alter the structure and function of the α-actinin-2 actin-binding domain

Atang

Rebbeck

Thomas

et al. 2023

Biochemical and Biophysical Research Communications

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Section: Human α-Actinin-2 Cardiomyopathy Missense Variants Attain Fo...mentioning

confidence: 53%

Cardiomyopathy-associated variants alter the structure and function of the α-actinin-2 actin-binding domain

Atang

Rebbeck

Thomas

et al. 2023

Biochemical and Biophysical Research Communications

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“…Specifically, it suggests that a small molecule drug that can alleviate high-affinity actin binding may be broadly useful as a SCA5 therapeutic. Recently we reported the identification of several small molecules capable of reducing binding of the L253P mutant to actin in vitro 38 . This established that the spectrin-actin interaction can be targeted by small molecules.…”

Section: Discussionmentioning

confidence: 99%

Increased actin binding is a shared molecular consequence of numerous spinocerebellar ataxia mutations in β-III-spectrin

Atang

Keller

Denha

et al. 2023

Preprint

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Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the SPTBN2 gene encoding the cytoskeletal protein β-III-spectrin. Previously, we demonstrated that a L253P missense mutation, localizing to the β-III-spectrin actin-binding domain (ABD), causes increased actin-binding affinity. Here we investigate the molecular consequences of nine additional ABD-localized, SCA5 missense mutations: V58M, K61E, T62I, K65E, F160C, D255G, T271I, Y272H, and H278R. We show that all of the mutations, similar to L253P, are positioned at or near the interface of the two calponin homology subdomains (CH1 and CH2) comprising the ABD. Using biochemical and biophysical approaches, we demonstrate that the mutant ABD proteins can attain a well-folded state. However, thermal denaturation studies show that all nine mutations are destabilizing, suggesting a structural disruption at the CH1-CH2 interface. Importantly, all nine mutations cause increased actin binding. The mutant actin-binding affinities vary greatly, and none of the nine mutations increase actin-binding affinity as much as L253P. ABD mutations causing high-affinity actin binding, with the notable exception of L253P, appear to be associated with early age of symptom onset. Altogether, the data indicate increased actin-binding affinity is a shared molecular consequence of numerous SCA5 mutations, which has important therapeutic implications.

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“…Specifically, it suggests that a small molecule drug that can alleviate high-affinity actin binding may be broadly useful as a SCA5 therapeutic. Recently, we reported the identification of several small molecules capable of reducing binding of the L253P mutant to actin in vitro [ 37 ]. This established that the spectrin-actin interaction can be targeted by small molecules.…”

Section: Discussionmentioning

confidence: 99%

Increased Actin Binding Is a Shared Molecular Consequence of Numerous SCA5 Mutations in β-III-Spectrin

Atang,

Keller,

Denha

et al. 2023

Cells

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Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the SPTBN2 gene encoding the cytoskeletal protein β-III-spectrin. Previously, we demonstrated that a L253P missense mutation, localizing to the β-III-spectrin actin-binding domain (ABD), causes increased actin-binding affinity. Here we investigate the molecular consequences of nine additional ABD-localized, SCA5 missense mutations: V58M, K61E, T62I, K65E, F160C, D255G, T271I, Y272H, and H278R. We show that all of the mutations, similar to L253P, are positioned at or near the interface of the two calponin homology subdomains (CH1 and CH2) comprising the ABD. Using biochemical and biophysical approaches, we demonstrate that the mutant ABD proteins can attain a well-folded state. However, thermal denaturation studies show that all nine mutations are destabilizing, suggesting a structural disruption at the CH1-CH2 interface. Importantly, all nine mutations cause increased actin binding. The mutant actin-binding affinities vary greatly, and none of the nine mutations increase actin-binding affinity as much as L253P. ABD mutations causing high-affinity actin binding, with the notable exception of L253P, appear to be associated with an early age of symptom onset. Altogether, the data indicate that increased actin-binding affinity is a shared molecular consequence of numerous SCA5 mutations, which has important therapeutic implications.

show abstract

Early-phase drug discovery of β-III-spectrin actin-binding modulators for treatment of spinocerebellar ataxia type 5

Cited by 5 publications

References 41 publications

Cardiomyopathy-associated variants alter the structure and function of the α-actinin-2 actin-binding domain

Cardiomyopathy-associated variants alter the structure and function of the α-actinin-2 actin-binding domain

Increased actin binding is a shared molecular consequence of numerous spinocerebellar ataxia mutations in β-III-spectrin

Increased Actin Binding Is a Shared Molecular Consequence of Numerous SCA5 Mutations in β-III-Spectrin

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