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WDR48 activates USP12. 65 / 66
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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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"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 ca[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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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 ca[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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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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"Mechanism of USP12 Activation by UAF1 and 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 )."
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"Together, these unique features of the Ub-free USP12 structures hint at possible involvement of the USP12 Fingers domain in enzyme regulation.To delineate the mechanism by which UAF1 activates USP12, [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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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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"Consistent with our results on USP1, activation of USP12-WDR20 by UAF1 is achieved mainly through an 20-fold increase of k cat with little change in K M , suggesting that substrate affinity of USP12 is not altered by UAF1 ( Figures 6A and S5A-S5D) ."
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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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"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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"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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"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 3.2 Å ()."
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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."
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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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"This result clearly indicates that UAF1 and WDR20 allosterically activate USP12 through two distinct pathways."
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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 3.2 Å (Table S1 )."
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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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"The WD-repeat protein WDR48 (USP1 associated factor UAF-1) stimulates activity of ubiquitin specific proteases USP1, USP12, and USP46."
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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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"WDR48 and UAF1 is an activator of USP1 and more recently has been shown to activate USP12 and USP46."
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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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"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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"With a mutation introduced to the BL1 residue F262, USP12 could no longer be activated by UAF1 but retained full WDR20-stimulated activity (D and 6E)."
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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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"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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"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."
27650958
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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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"Interestingly, USP12 and USP46 are activated by two β-propeller proteins, UAF1, and WDR20."
32512887
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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."
27373336
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"Together, these unique features of the Ub-free USP12 structures hint at possible involvement of the USP12 Fingers domain in enzyme regulation.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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"Interestingly, USP12 and USP46 are activated by two β-propeller proteins, UAF1, and WDR20."
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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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"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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"Uaf-1 and WDR20 have previously been shown to stimulate Usp12 catalytic activity [XREF_BIBR, XREF_BIBR]."
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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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"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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"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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"This result clearly indicates that UAF1 and WDR20 indeed allosterically activate USP12 through two distinct pathways."
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"This study confirmed that the modulator UAF1 activates USP1, USP12, and USP46, and GMPS activates USP7."
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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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"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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"The distinct binding sites and synergistic effect of the two propeller proteins on USP12 raise the question of whether UAF1 and WDR20 activate USP12 via two independent or converging allosteric pathwa[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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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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"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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"This result clearly indicates that UAF1 and WDR20 allosterically activate USP12 through two distinct pathways."
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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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"UAF1 stimulates not only USP1, but also two other DUB enzymes, USP12 and USP46."
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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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"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 ()."
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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-fold increase of k with little change in K, suggesting that substrate affinity of USP12 is not [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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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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"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 (Figures 6A and S6) ."
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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 (Cohn et al., 2007, 2009; Faesen et al., 2011)."
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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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"A Schematic Model of USP12 Activation by UAF1 and WDR20Cartoon representations of the right-hand-shaped free and activator-bound USP12 and their substrate-bound forms."
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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."
27373336
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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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"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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"WDR48 stimulates the activity of three DUBs, USP12, USP46 and USP1, a DUB which regulates the Fanconi anemia DNA damage pathway (Cohn et al., 2007 (Cohn et al., , 2009 Faesen et al., 2011) ."
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"This result clearly indicates that UAF1 and WDR20 indeed allosterically activate USP12 through two distinct pathways."
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