![]() ![]() Multiple Ub moieties can be covalently linked together to form chains on the substrate via one of the seven lysine side chains or the free amino terminus of Ub. Ubiquitination is the process whereby the small protein ubiquitin (Ub) is covalently attached to a substrate protein via a cascade of three (E1-E2-E3) enzymes. 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. We also developed and characterized three ubiquitin variant (UbV) inhibitors that selectively engage distinct binding sites in USP37. In the case of K48-linked ubiquitin chains this potentiation stemmed largely from a dramatic increase in catalytic rate (k cat). 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. ![]() We investigated the role of the three UIMs in the ability of USP37 to cleave di-ubiquitin chains. USP37 contains a unique insert of three ubiquitin interacting motifs (UIMs) within its catalytic DUB domain. USP37 is a deubiquitinase (DUB) with roles in the regulation of DNA damage repair and the cohesion of sister chromatids during mitosis. ![]()
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