Abstract:
:Deubiquitinating enzymes (DUBs) control vital processes in eukaryotes by hydrolyzing ubiquitin adducts. Their activities are tightly regulated, but the mechanisms remain elusive. In particular, the DUB UCH-L5 can be either activated or inhibited by conserved regulatory proteins RPN13 and INO80G, respectively. Here we show how the DEUBAD domain in RPN13 activates UCH-L5 by positioning its C-terminal ULD domain and crossover loop to promote substrate binding and catalysis. The related DEUBAD domain in INO80G inhibits UCH-L5 by exploiting similar structural elements in UCH-L5 to promote a radically different conformation, and employs molecular mimicry to block ubiquitin docking. 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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Sahtoe DD,van Dijk WJ,El Oualid F,Ekkebus R,Ovaa H,Sixma TKdoi
10.1016/j.molcel.2014.12.039subject
Has Abstractpub_date
2015-03-05 00:00:00pages
887-900issue
5eissn
1097-2765issn
1097-4164pii
S1097-2765(14)01017-Xjournal_volume
57pub_type
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