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The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP

The spinocerebellar ataxias (SCAs) are a class of incurable diseases characterized by degeneration of the cerebellum that results in movement disorder. Recently, a new heritable form of SCA, spinocerebellar ataxia type 48 (SCA48), was attributed to dominant mutations in STIP1 homology and U box-cont...

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Autores principales: Umano, A., Fang, K., Qu, Z., Scaglione, J.B., Altinok, S., Treadway, C.J., Wick, E.T., Paulakonis, E., Karunanayake, C., Chou, S., Bardakjian, T.M., Gonzalez-Alegre, P., Page, R.C., Schisler, J.C., Brown, N.G., Yan, D., Scaglione, K.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097460/
https://www.ncbi.nlm.nih.gov/pubmed/35398354
http://dx.doi.org/10.1016/j.jbc.2022.101899
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author Umano, A.
Fang, K.
Qu, Z.
Scaglione, J.B.
Altinok, S.
Treadway, C.J.
Wick, E.T.
Paulakonis, E.
Karunanayake, C.
Chou, S.
Bardakjian, T.M.
Gonzalez-Alegre, P.
Page, R.C.
Schisler, J.C.
Brown, N.G.
Yan, D.
Scaglione, K.M.
author_facet Umano, A.
Fang, K.
Qu, Z.
Scaglione, J.B.
Altinok, S.
Treadway, C.J.
Wick, E.T.
Paulakonis, E.
Karunanayake, C.
Chou, S.
Bardakjian, T.M.
Gonzalez-Alegre, P.
Page, R.C.
Schisler, J.C.
Brown, N.G.
Yan, D.
Scaglione, K.M.
author_sort Umano, A.
collection PubMed
description The spinocerebellar ataxias (SCAs) are a class of incurable diseases characterized by degeneration of the cerebellum that results in movement disorder. Recently, a new heritable form of SCA, spinocerebellar ataxia type 48 (SCA48), was attributed to dominant mutations in STIP1 homology and U box-containing 1 (STUB1); however, little is known about how these mutations cause SCA48. STUB1 encodes for the protein C terminus of Hsc70 interacting protein (CHIP), an E3 ubiquitin ligase. CHIP is known to regulate proteostasis by recruiting chaperones via a N-terminal tetratricopeptide repeat domain and recruiting E2 ubiquitin-conjugating enzymes via a C-terminal U-box domain. These interactions allow CHIP to mediate the ubiquitination of chaperone-bound, misfolded proteins to promote their degradation via the proteasome. Here we have identified a novel, de novo mutation in STUB1 in a patient with SCA48 encoding for an A52G point mutation in the tetratricopeptide repeat domain of CHIP. Utilizing an array of biophysical, biochemical, and cellular assays, we demonstrate that the CHIP(A52G) point mutant retains E3-ligase activity but has decreased affinity for chaperones. We further show that this mutant decreases cellular fitness in response to certain cellular stressors and induces neurodegeneration in a transgenic Caenorhabditis elegans model of SCA48. Together, our data identify the A52G mutant as a cause of SCA48 and provide molecular insight into how mutations in STUB1 cause SCA48.
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spelling pubmed-90974602022-05-18 The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP Umano, A. Fang, K. Qu, Z. Scaglione, J.B. Altinok, S. Treadway, C.J. Wick, E.T. Paulakonis, E. Karunanayake, C. Chou, S. Bardakjian, T.M. Gonzalez-Alegre, P. Page, R.C. Schisler, J.C. Brown, N.G. Yan, D. Scaglione, K.M. J Biol Chem Research Article The spinocerebellar ataxias (SCAs) are a class of incurable diseases characterized by degeneration of the cerebellum that results in movement disorder. Recently, a new heritable form of SCA, spinocerebellar ataxia type 48 (SCA48), was attributed to dominant mutations in STIP1 homology and U box-containing 1 (STUB1); however, little is known about how these mutations cause SCA48. STUB1 encodes for the protein C terminus of Hsc70 interacting protein (CHIP), an E3 ubiquitin ligase. CHIP is known to regulate proteostasis by recruiting chaperones via a N-terminal tetratricopeptide repeat domain and recruiting E2 ubiquitin-conjugating enzymes via a C-terminal U-box domain. These interactions allow CHIP to mediate the ubiquitination of chaperone-bound, misfolded proteins to promote their degradation via the proteasome. Here we have identified a novel, de novo mutation in STUB1 in a patient with SCA48 encoding for an A52G point mutation in the tetratricopeptide repeat domain of CHIP. Utilizing an array of biophysical, biochemical, and cellular assays, we demonstrate that the CHIP(A52G) point mutant retains E3-ligase activity but has decreased affinity for chaperones. We further show that this mutant decreases cellular fitness in response to certain cellular stressors and induces neurodegeneration in a transgenic Caenorhabditis elegans model of SCA48. Together, our data identify the A52G mutant as a cause of SCA48 and provide molecular insight into how mutations in STUB1 cause SCA48. American Society for Biochemistry and Molecular Biology 2022-04-07 /pmc/articles/PMC9097460/ /pubmed/35398354 http://dx.doi.org/10.1016/j.jbc.2022.101899 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Umano, A.
Fang, K.
Qu, Z.
Scaglione, J.B.
Altinok, S.
Treadway, C.J.
Wick, E.T.
Paulakonis, E.
Karunanayake, C.
Chou, S.
Bardakjian, T.M.
Gonzalez-Alegre, P.
Page, R.C.
Schisler, J.C.
Brown, N.G.
Yan, D.
Scaglione, K.M.
The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP
title The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP
title_full The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP
title_fullStr The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP
title_full_unstemmed The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP
title_short The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP
title_sort molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase chip
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097460/
https://www.ncbi.nlm.nih.gov/pubmed/35398354
http://dx.doi.org/10.1016/j.jbc.2022.101899
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