β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity
Abstract 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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-05762-2 |
| _version_ | 1818887698005360640 |
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| author | Sarah A. Denha Alexandra E. Atang Thomas S. Hays Adam W. Avery |
| author_facet | Sarah A. Denha Alexandra E. Atang Thomas S. Hays Adam W. Avery |
| author_sort | Sarah A. Denha |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-19T16:41:21Z |
| format | Article |
| id | doaj.art-46b4e8567b9142cfb5b041cfd820729c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T16:41:21Z |
| publishDate | 2022-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-46b4e8567b9142cfb5b041cfd820729c2022-12-21T20:13:47ZengNature PortfolioScientific Reports2045-23222022-02-0112111110.1038/s41598-022-05762-2β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicitySarah A. Denha0Alexandra E. Atang1Thomas S. Hays2Adam W. Avery3Department of Chemistry, Oakland UniversityDepartment of Chemistry, Oakland UniversityDepartment of Genetics, Cell Biology and Development, University of MinnesotaDepartment of Chemistry, Oakland UniversityAbstract 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.https://doi.org/10.1038/s41598-022-05762-2 |
| spellingShingle | Sarah A. Denha Alexandra E. Atang Thomas S. Hays Adam W. Avery β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity Scientific Reports |
| title | β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity |
| title_full | β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity |
| title_fullStr | β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity |
| title_full_unstemmed | β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity |
| title_short | β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity |
| title_sort | β iii spectrin n terminus is required for high affinity actin binding and sca5 neurotoxicity |
| url | https://doi.org/10.1038/s41598-022-05762-2 |
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