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Crystal structure of a Josephin-ubiquitin complex: evolutionary restraints on ataxin-3 deubiquitinating activity
Journal article   Open access   Peer reviewed

Crystal structure of a Josephin-ubiquitin complex: evolutionary restraints on ataxin-3 deubiquitinating activity

Stephen D Weeks, Kimberly C Grasty, Lisa Hernandez-Cuebas and Patrick J Loll
The Journal of biological chemistry, v 286(6), pp 4555-4565
11 Feb 2011
DOI: https://doi.org/10.1074/jbc.M110.177360
PMID: 21118805
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1074/jbc.M110.177360View
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Abstract

Ataxin-3 Ubiquitin - metabolism Crystallography, X-Ray Multiprotein Complexes - genetics Structure-Activity Relationship Multiprotein Complexes - metabolism Endopeptidases - chemistry Nerve Tissue Proteins - chemistry Protein Structure, Quaternary Nuclear Proteins - genetics Repressor Proteins - metabolism Protein Structure, Tertiary Endopeptidases - metabolism Repressor Proteins - chemistry Ubiquitin - chemistry Repressor Proteins - genetics Nuclear Proteins - metabolism Ubiquitin - genetics Nuclear Proteins - chemistry Nerve Tissue Proteins - genetics Protein Folding Nerve Tissue Proteins - metabolism Multiprotein Complexes - chemistry Endopeptidases - genetics Protein Binding Evolution, Molecular
The Josephin domain is a conserved cysteine protease domain found in four human deubiquitinating enzymes: ataxin-3, the ataxin-3-like protein (ATXN3L), Josephin-1, and Josephin-2. Josephin domains from these four proteins were purified and assayed for their ability to cleave ubiquitin substrates. Reaction rates differed markedly both among the different proteins and for different substrates with a given protein. The ATXN3L Josephin domain is a significantly more efficient enzyme than the ataxin-3 domain despite their sharing 85% sequence identity. To understand the structural basis of this difference, the 2.6 Å x-ray crystal structure of the ATXN3L Josephin domain in complex with ubiquitin was determined. Although ataxin-3 and ATXN3L adopt similar folds, they bind ubiquitin in different, overlapping sites. Mutations were made in ataxin-3 at selected positions, introducing the corresponding ATXN3L residue. Only three such mutations are sufficient to increase the catalytic activity of the ataxin-3 domain to levels comparable with that of ATXN3L, suggesting that ataxin-3 has been subject to evolutionary restraints that keep its deubiquitinating activity in check.

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Web of Science research areas
Biochemistry & Molecular Biology
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