IndraLab

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Proteasome activates USP14. 24 / 25
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"As the NMR chemical shift characteristics in response to the functional mutations agree well with the presence of functionally coupled regions (Papaleo et al., 2016; Selvaratnam et al., 2011; Skeens & Lisi, 2023; Xu et al., 2019), it is a tenable hypothesis that USP14 activation by the proteasome could be allosterically mediated through this dynamic network.3 DISCUSSION."
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"USP14 activation by the proteasome."
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"To confirm this, we tested TRIM11 on recombinant USP14 protein that were activated by proteasome enriched cell lysates or purified RPs."
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"Again, this proteasome mediated USP14 activation was effectively prevented by recombinant TRIM11."
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"53 The binding of proteasome causes considerable conformational change in USP14 with the translocation of two surface loops (BL1 and BL2) that block the catalytic site."
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"1 This work elucidated for the first time the molecular mechanism of human USP14 activation by the proteasome and how this is mutually translated into proteasome regulation at the atomic level.4 CONTROL OF THE PROTEASOME REVEALS THERAPEUTIC TARGETS."
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"USP14 activation by the proteasome."
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"This suggests that a unique negative feedback model, in which USP14 is activated by proteasome and then proteasomal degradation is suppressed by deubiquitination, is the basis by which USP14 serves as a critical inhibitory component of the proteasome [ xref , xref , xref ]."
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"Still, USP14 activity can be remarkably enhanced by association with the proteasome -- up to ~ 800-fold -- suggesting its major regulatory role in proteasome function [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"This suggests that a unique negative feedback model, in which USP14 is activated by proteasome and then proteasomal degradation is suppressed by deubiquitination, is the basis by which USP14 serves as a critical inhibitory component of the proteasome [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"Indeed, phosphorylation of Usp14 (or the use of a Usp14 phosphomimetic) results in increased activity in assays with the fluorogenic substrate ubiquitin-7-amino-4-methylcoumarin (Ub-AMC), for both Usp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Should an unfolded or loosely folded initiation region of the substrate be available xref , substrate insertion into the AAA-ATPase channel can stochastically occur before USP14 activation by the proteasome, which presumably depends on the specific structures of substrate-ubiquitin conjugates."
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"The 26S proteasome-activated USP14 is capable of cleaving single ubiquitin from its substrates and removing the en-bloc ubiquitin chains from substrates ubiquitinated at multiple sites, until only a single chain remains ( xref )."
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"The resolution of this conundrum required the identification of a preferred substrate of Usp14 and of the properties that govern substrate preference.Cyclin B, ubiquitinated by its physiological ligas[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In an impressive, technically challenging study, Zhang and Zou et al. used time-resolved cryo-electron microscopy (EM) to study 13 distinct proteasome conformational states [ 6 ], providing the most d[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Based on the structure of USP14, several inhibitors with high potency and selectivity, such as IU1 and IU1 derivatives, have been discovered and characterized for their ability to inhibit 26S proteasome-activated USP14 in an allosteric manner at both cellular and in vivo levels."
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"USP14 can be activated by the 26S proteasome."
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"In contrast to these inhibitory effects, USP14 activates the gate opening of the 26S proteasome when it is bound by ubiquitin chains which induces a conformational switch in USP14 (Peth et al, 2013; Kuo & Goldberg, 2017; Hung et al, 2022)."
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"XREF_FIG shows that free chains of diverse length and linkage type are all cleaved minimally by proteasome activated USP14, even upon long incubation."
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"As the NMR chemical shift characteristics in response to the functional mutations agree well with the presence of functionally coupled regions (Papaleo et al.,  xref ; Selvaratnam et al.,  xref ; Skeens & Lisi,  xref ; Xu et al.,  xref ), it is a tenable hypothesis that USP14 activation by the proteasome could be allosterically mediated through this dynamic network."
40095364
sparser
"Based on the structure of USP14, several inhibitors with high potency and selectivity, such as IU1 and IU1 derivatives, have been discovered and characterized for their ability to inhibit 26S proteasome-activated USP14 in an allosteric manner at both cellular and in vivo levels."
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"It is different from the mechanism by which the proteasome activates USP14."
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"This is consistent with previous studies showing that PGJ2 lowers 26S proteasome levels and activity [XREF_BIBR, XREF_BIBR], and inhibits some of the thiol deubiquitinases including UCH-L1 and UCH-L3 [XREF_BIBR, XREF_BIBR], as well as Ub-isopeptidase activity [XREF_BIBR], but not USP14 as shown here in our current studies."
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"The 26S proteasome-activated USP14 is capable of cleaving single ubiquitin from its substrates and removing the en-bloc ubiquitin chains from substrates ubiquitinated at multiple sites, until only a single chain remains (Lee et al., 2016)."
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