The ubiquitin interacting motifs of USP37 act on the proximal Ub of a di-Ub chain to enhance catalytic efficiency.

Autor:	Manczyk N; Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada., Veggiani G; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Banting and Best Department of Medical Research, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada., Teyra J; Banting and Best Department of Medical Research, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada., Strilchuk AW; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada., Sidhu SS; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. sachdev.sidhu@utoronto.ca.; Banting and Best Department of Medical Research, Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada. sachdev.sidhu@utoronto.ca., Sicheri F; Department of Biochemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada. sicheri@lunenfeld.ca.; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada. sicheri@lunenfeld.ca.; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada. sicheri@lunenfeld.ca.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2019 Mar 11; Vol. 9 (1), pp. 4119. Date of Electronic Publication: 2019 Mar 11.
DOI:	10.1038/s41598-019-40815-z
Abstrakt:	USP37 is a deubiquitinase (DUB) with roles in the regulation of DNA damage repair and the cohesion of sister chromatids during mitosis. USP37 contains a unique insert of three ubiquitin interacting motifs (UIMs) within its catalytic DUB domain. We investigated the role of the three UIMs in the ability of USP37 to cleave di-ubiquitin chains. We found that the third UIM of USP37 recognizes the proximal ubiquitin moiety of K48 di-Ub to potentiate cleavage activity and posit that this mechanism of action may be generalizable to other chain types. In the case of K48-linked ubiquitin chains this potentiation stemmed largely from a dramatic increase in catalytic rate (k cat ). We also developed and characterized three ubiquitin variant (UbV) inhibitors that selectively engage distinct binding sites in USP37. In addition to validating the deduced functional roles of the three UIMs in catalysis, the UbVs highlight a novel and effective means to selectively inhibit members of the difficult to drug DUB family.
Databáze:	MEDLINE
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