IndraLab

Statements

UAF1 activates USP12. 10 / 10
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"To gain deeper mechanistic insights into USP12 activation by UAF1 and WDR20 , we first determined the steady-state kinetics of substrate hydrolysis by USP12 in different forms ."
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"Activation of USP12 by UAF1 requires structural fine-tuning at the junction of the Ub globular domain and it tail through BL1 , whereas WDR20 acts independently of this site and directly affects the catalytic cleft ."
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"With a mutation introduced to the BL1 residue F262 , USP12 could no longer be activated by UAF1 but retained full WDR20-stimulated activity ( Figures 6D and 6E ) ."
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"Nevertheless , the free USP12 structure alone is insufficient to link these predicted changes to USP12 activation by UAF1 or WDR20 ."
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"To delineate the mechanism by which UAF1 activates USP12 , we next determined the crystal structure of USP12 in a complex with full-length human UAF1 in the F222 space group at 3 ."
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"This result clearly indicates that UAF1 and WDR20 allosterically activate USP12 through two distinct pathways ."
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"Highlights d Free USP12 deubiquitinase is inactive and has several flexible structural elements d UAF1 and WDR20 can both activate USP12 without increasing its substrate affinity d UAF1 and WDR20 bind USP12 at two distinct sites away from its catalytic center d Two distinct allosteric mechanisms underlie USP12 activation by UAF1 and WDR20 Ubiquitin-specific proteases ( USPs ) constitute the largest family of deubiquitinating enzymes , whose catalytic competency is often modulated by their binding partners through unknown mechanisms ."
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"First , our results rule out the possibility that UAF1 and WDR20 activate USP12 by enhancing its substrate affinity ."
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"Based on our results , we propose a tenable model for USP12 activation by UAF1 and WDR20 ( Figure 7 ) ."
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"UAF1 activates USP12 by binding to the tip of its Fingers domain and transmitting a long-range allosteric signal to BL1 ."
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