6qml
From Proteopedia
UCHL3 in complex with synthetic, K27-linked diubiquitin
Structural highlights
FunctionUCHL3_HUMAN Deubiquitinating enzyme (DUB) that controls levels of cellular ubiquitin through processing of ubiquitin precursors and ubiquitinated proteins. Thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of either ubiquitin or NEDD8. Has a 10-fold preference for Arg and Lys at position P3", and exhibits a preference towards 'Lys-48'-linked Ubiquitin chains. Deubiquitinates ENAC in apical compartments, thereby regulating apical membrane recycling. Indirectly increases the phosphorylation of IGFIR, AKT and FOXO1 and promotes insulin-signaling and insulin-induced adipogenesis. Required for stress-response retinal, skeletal muscle and germ cell maintenance. May be involved in working memory. Can hydrolyze UBB(+1), a mutated form of ubiquitin which is not effectively degraded by the proteasome and is associated with neurogenerative disorders.[1] [2] [3] [4] [5] Publication Abstract from PubMedFunctional analysis of lysine 27-linked ubiquitin chains ((K27)Ub) is difficult due to the inability to make them through enzymatic methods and due to a lack of model tools and substrates. Here we generate a series of ubiquitin (Ub) tools to study how the deubiquitinase UCHL3 responds to (K27)Ub chains in comparison to lysine 63-linked chains and mono-Ub. From a crystal structure of a complex between UCHL3 and synthetic (K27)Ub2, we unexpectedly discover that free (K27)Ub2 and (K27)Ub2-conjugated substrates are natural inhibitors of UCHL3. Using our Ub tools to profile UCHL3's activity, we generate a quantitative kinetic model of the inhibitory mechanism and we find that (K27)Ub2 can inhibit UCHL3 covalently, by binding to its catalytic cysteine, and allosterically, by locking its catalytic loop tightly in place. Based on this inhibition mechanism, we propose that UCHL3 and (K27)Ub chains likely sense and regulate each other in cells. K27-Linked Diubiquitin Inhibits UCHL3 via an Unusual Kinetic Trap.,van Tilburg GBA, Murachelli AG, Fish A, van der Heden van Noort GJ, Ovaa H, Sixma TK Cell Chem Biol. 2021 Feb 18;28(2):191-201.e8. doi:, 10.1016/j.chembiol.2020.11.005. Epub 2020 Nov 24. PMID:33238157[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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