IndraLab

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WDR48 activates USP12. 48 / 49
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"Together, UAF1 and WDR20 are able to synergistically stimulate the enzymatic activities of USP12 and USP46 to a peak level."
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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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"WDR48 stimulates the activity of the deubiquitylases USP1, USP12 and USP46."
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"Ning Zheng (USA) presented molecular studies of USP12, revealing that UAF1 and WDR20 potentiate USP12 catalytic activity."
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"For example, USP1, USP12, and USP46 are activated by the WD40-repeat containing UAF1, and USP7 is activated by GMPS (Cohn et al., 2007, 2009; Faesen et al., 2011; van der Knaap et al., 2005)."
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"To delineate the mechanism by which UAF1 activates USP12, we next determined the crystal structure of USP12 in complex with full-length human UAF1 in F222 space group at 3.2 A (XREF_SUPPLEMENTARY)."
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"Wild type UAF1 was unable to activate USP12 E190K to similar levels as compared to USP12 WT ( xref d, e) and similarly, the UAF1 3X mutant did no longer activate."
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"USP12 and USP46, consisting of only a USP domain [4], share 88% amino acid sequence homology and are potentiated by WDR48, WDR20, and DMWD [8, 9, 10]."
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"This study confirmed that the modulator UAF1 activates USP1, USP12, and USP46, and GMPS activates USP7."
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"WDR48, with the high score in our LC-MS/MS results, is reported as a cofactor to increase the enzymatic activity of USP1, USP12 and USP46, but could not modify the affinity of the DUBs and their subst[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Therefore, this suggests that for some USPs the KG FP reagent may be a better substrate, and provide more relevant kinetic parameters.This study confirmed that the modulator UAF1 activates USP1, USP12[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In agreement with our enzyme kinetics data, our binding studies revealed negligible changes in the substrate binding affinity of USP12 induced by UAF1 or WDR20 (XREF_FIG and XREF_SUPPLEMENTARY)."
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"Although mammalian USP46 and USP12 DUB activity can be stimulated by two proteins UAF-1 and WDR20, the C. elegans homologs of these genes have not yet been identified."
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"WDR48 stimulates the activity of three DUBs, USP12, USP46 and USP1, a DUB which regulates the Fanconi anemia DNA damage pathway."
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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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"The distinct binding sites and synergistic effect of the two propeller proteins on USP12 raises the question of whether UAF1 and WDR20 activate USP12 via two independent or converging allosteric pathways."
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"This result clearly indicates that UAF1 and WDR20 indeed allosterically activate USP12 through two distinct pathways."
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"Activation of USP12 by UAF1 requires a structural fine tuning at the junction of Ub globular domain and it tail through BL1, whereas WDR20 acts independently of this site and directly impacts the catalytic cleft."
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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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"UAF1 also binds and activates two other DUBs, USP12 and USP46 ( xref ), and studies that reveal how UAF1 binds and activates USP12 and USP46 suggest that UAF1 will bind to USP1 in an analogous manner ( xref , xref )."
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"Both WDR48 and WDR20 stimulate USP12 and USP46 catalytic activity (k cat) without increasing substrate binding affinity, suggesting that the WDR proteins may affect DUB activity via a novel structural mechanism."
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"However, as shown previously for USP46/UAF1 ( xref ), the combination of these complementary mutants rescues the activation ( xref f), highlighting the importance of the fingers sub domain in USP12 and USP46 ( xref ) activation by UAF1."
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"Thus it is very hard to envision from these structures how USP12 is activated by UAF1, especially when the activation is due to an increase in k cat and not K M . It is possible that UAF1 binding stabilizes the flexible USP12 “fingers”, transforming it into a catalytically proficient state and this may not be visible since we compare it to a ubiquitin-bound USP structure."
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"WDR20 and UAF1 potentiate the activity of USP12 and USP46 by allosterically increasing their catalytic efficiency without increasing their substrate-binding affinity ."
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"It has also been shown that UAF1 activation of USP12 is mainly caused by a series of subtle structural rearrangements in various parts of the enzyme."
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"The Michaelis Menten parameters K cat and K M did not change with higher UAF1 concentration, confirming that only Interface 1 is important for UAF1 mediated USP12 activation (XREF_TABLE)."
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"The free USP12 structure alone, nevertheless, is insufficient to link these predicted changes to USP12 activation by UAF1 or WDR20."
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"In addition, whereas USP1 cannot interact with WDR20, USP12, and USP46 may; further WDR48 and WDR20 can both independently and cooperatively stimulate the activities of USP12 and USP46."
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"Mechanism of USP12 Activation by UAF1 and WDR20."
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"Uaf-1 and WDR20 have previously been shown to stimulate Usp12 catalytic activity [XREF_BIBR, XREF_BIBR]."
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"Based on our result, we propose a tenable model for USP12 activation by UAF1 and WDR20 ( xref )."
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"To delineate the mechanism by which UAF1 activates USP12, we next determined the crystal structure of USP12 in complex with full-length human UAF1 in F222 space group at 3.2 Å ( xref )."
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"Two closely related DUBs, USP12 and USP46, are similarly activated by UAF-1, but unlike USP1, these can be hyperactivated by another WD40 repeat protein, named WDR20 [52–54] ."
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"Reduction of Uaf-1 diminished the levels of Usp12 transcripts in the LNCaP-AI and VCaP cell lines."
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"The human deubiquitinase, ubiquitin-specific peptidase 12 (USP12), acts as a tumor suppressor and is catalytically activated by USP1-associated factor 1 (UAF1) and WDR20."
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"In USP12, this loop is important for activation, as mutation of a stretch of glycine residues within the loop leads to loss in activation of USP12 by either UAF1 or WDR20."
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"Consistent with our results on USP1, activation of USP12-WDR20 by UAF1 is achieved mainly through an ~20 folds increase of k cat with little changes in K M , suggesting that substrate affinity of USP12 is not altered by UAF1 ( xref , xref )."
27373336
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"The distinct binding sites and synergistic effect of the two propeller proteins on USP12 raises the question of whether UAF1 and WDR20 activate USP12 via two independent or converging allosteric pathways."
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"UAF1 activation of USP12 requires structural fine-tuning at the ubiquitin-binding site, while WDR20 directly regulates the catalytic center of the enzyme remotely, transforming USP12 into a compact structure similar to USP46-Ub [ xref ]."
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"WDR48 and UAF1 is an activator of USP1 and more recently has been shown to activate USP12 and USP46."
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"Remarkably, with a mutation introduced to a BL1 residue, F262, USP12 could no longer be activated by UAF1, but retained full WDR20-stimulated activity ( xref , xref )."
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"This result clearly indicates that UAF1 and WDR20 indeed allosterically activate USP12 through two distinct pathways."
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"Interestingly, USP12 and USP46 are activated by two β-propeller proteins, UAF1, and WDR20."
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"Activation of USP12 by UAF1 requires a structural fine-tuning at the junction of Ub globular domain and it tail through BL1, whereas WDR20 acts independently of this site and directly impacts the catalytic cleft."
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"Interestingly, USP12 and USP46 are activated by two β-propeller proteins, UAF1, and WDR20."
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"Thus it is very hard to envision from these structures how USP12 is activated by UAF1, especially when the activation is due to an increase in k cat and not K M."
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"These findings raised the possibility that, like their yeast counterparts, human UAF1 and WDR20 might modulate subcellular localization of USP12 and USP46 and, furthermore, that cofactor binding might[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"UAF1 stimulates not only USP1, but also two other DUB enzymes, USP12 and USP46."
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