Structures of ubiquitin-like (Ubl) and Hsp90-like domains of sacsin provide insight into pathological mutations

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease that is caused by mutations in the SACS gene. The product of this gene is a very large 520-kDa cytoplasmic protein, sacsin, with a ubiquitin-like (Ubl) domain at the N terminus followed by three large s...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 293; no. 33; pp. 12832 - 12842
Main Authors:	Ménade, Marie, Kozlov, Guennadi, Trempe, Jean-François, Pande, Harshit, Shenker, Solomon, Wickremasinghe, Sihara, Li, Xinlu, Hojjat, Hamed, Dicaire, Marie-Josée, Brais, Bernard, McPherson, Peter S., Wong, Michael J.H., Young, Jason C., Gehring, Kalle
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 17-08-2018 American Society for Biochemistry and Molecular Biology
Subjects:	Amino Acid Substitution ARSACS disease biophysics crystal structure Crystallography, X-Ray Heat-Shock Proteins - chemistry Heat-Shock Proteins - genetics Heat-Shock Proteins - metabolism Hsp90 Humans molecular chaperone Muscle Spasticity - genetics Muscle Spasticity - metabolism Mutation, Missense neurodegenerative disease Protein Domains Protein Folding Protein Structure and Folding sacsin protein Spinocerebellar Ataxias - congenital Spinocerebellar Ataxias - genetics Spinocerebellar Ataxias - metabolism structural biology TRAP1 X-ray crystallography Hsp90 X-ray crystallography sacsin protein TRAP1 molecular chaperone neurodegenerative disease crystal structure structural biology ARSACS disease biophysics
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Summary:	Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease that is caused by mutations in the SACS gene. The product of this gene is a very large 520-kDa cytoplasmic protein, sacsin, with a ubiquitin-like (Ubl) domain at the N terminus followed by three large sacsin internal repeat (SIRPT) supradomains and C-terminal J and HEPN domains. The SIRPTs are predicted to contain Hsp90-like domains, suggesting a potential chaperone activity. In this work, we report the structures of the Hsp90-like Sr1 domain of SIRPT1 and the N-terminal Ubl domain determined at 1.55- and 2.1-Å resolutions, respectively. The Ubl domain crystallized as a swapped dimer that could be relevant in the context of full-length protein. The Sr1 domain displays the Bergerat protein fold with a characteristic nucleotide-binding pocket, although it binds nucleotides with very low affinity. The Sr1 structure reveals that ARSACS-causing missense mutations (R272H, R272C, and T201K) disrupt protein folding, most likely leading to sacsin degradation. This work lends structural support to the view of sacsin as a molecular chaperone and provides a framework for future studies of this protein.
Bibliography:	These authors contributed equally to this work. Present address: Dept. of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada. Edited by George N. DeMartino
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.RA118.003939