1. Structures of ubiquitin-like (Ubl) and Hsp90-like domains of sacsin provide insight into pathological mutations
- Author
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Jason C. Young, Kalle Gehring, Jean-François Trempe, Sihara Wickremasinghe, Marie Ménade, Xinlu Li, Hamed Hojjat, Marie-Josée Dicaire, Bernard Brais, Guennadi Kozlov, Michael J.H. Wong, Peter S. McPherson, Harshit Pande, and Solomon Shenker
- Subjects
0301 basic medicine ,Protein Folding ,Mutation, Missense ,Crystallography, X-Ray ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,Ubiquitin ,Humans ,Spinocerebellar Ataxias ,Missense mutation ,Molecular Biology ,Gene ,Heat-Shock Proteins ,biology ,Chemistry ,Cell Biology ,Hsp90 ,Cell biology ,N-terminus ,030104 developmental biology ,Amino Acid Substitution ,Structural biology ,Muscle Spasticity ,Chaperone (protein) ,Protein Structure and Folding ,biology.protein ,Protein folding ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2018