Mechanism of UCH-L5 activation and inhibition by DEUBAD domains in RPN13 and INO80G.
Bottom Line: In this process, large conformational changes create small but highly specific interfaces that mediate activity modulation of UCH-L5 by altering the affinity for substrates.Our results establish how related domains can exploit enzyme conformational plasticity to allosterically regulate DUB activity.These allosteric sites may present novel insights for pharmaceutical intervention in DUB activity.
Affiliation: Division of Biochemistry and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.Show MeSH
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Mentions: Strikingly, the UCH-L5∼UbPrg/INO80Gshort crystal structure resembled the activated RPN13DEU complex rather than the inhibited state (Figures 6A, S4A, and S4B). In this complex, the ULD largely reverted to the conformation seen in the activated RPN13DEU complexes with an extended helix α10 (Figure S4C). All conformational changes in UCH-L5 required to create the canonical ubiquitin-binding mode were also in place (Figures S4D and S4E). The structure of INO80Gshort itself and its binding mode to UCH-L5 were moreover identical to INO80GDEU (apart from FRF hairpin and α5-6) and RPN13DEU (Figure S4F).
Affiliation: Division of Biochemistry and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.