β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity.
β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity.
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DOI：
10.1038/s41598-022-05762-2
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发表时间：
2022-02-02
影响因子：
4.6
通讯作者：
Avery AW
中科院分区：
文献类型：
--
作者：
Denha SA;Atang AE;Hays TS;Avery AW
Recent structural studies of β-III-spectrin and related cytoskeletal proteins revealed N-terminal sequences that directly bind actin. These sequences are variable in structure, and immediately precede a conserved actin-binding domain composed of tandem calponin homology domains (CH1 and CH2). Here we investigated in Drosophila the significance of the β-spectrin N-terminus, and explored its functional interaction with a CH2-localized L253P mutation that underlies the neurodegenerative disease spinocerebellar ataxia type 5 (SCA5). We report that pan-neuronal expression of an N-terminally truncated β-spectrin fails to rescue lethality resulting from a β-spectrin loss-of-function allele, indicating that the N-terminus is essential to β-spectrin function in vivo. Significantly, N-terminal truncation rescues neurotoxicity and defects in dendritic arborization caused by L253P. In vitro studies show that N-terminal truncation eliminates L253P-induced high-affinity actin binding, providing a mechanistic basis for rescue. These data suggest that N-terminal sequences may be useful therapeutic targets for small molecule modulation of the aberrant actin binding associated with SCA5 β-spectrin and spectrin-related disease proteins.
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DOI：
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影响因子：
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