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WDR20 binds USP12 and WDR48. 26 / 26
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"During revision of this manuscript, a structure for the USP12, UAF1, and WDR20 complex was published."
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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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"Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center."
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"Binding of WDR20 to the UAF1-USP12 complex induces multiple structural changes in the enzyme, converting it into a compact form similar to Ub-bound USP46."
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"Our data suggest that the USP12, UAF1, and WDR20 complex dynamically shuttles between the plasma membrane, cytoplasm and nucleus."
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"Structural Comparisons of Activator-Bound USP12 and Ub-Conjugated USP46(A) Superposition of UAF1-bound USP12 and UAF1-WDR20-bound USP12 highlighting stabilization of BL1 and BL3 in the ternary complex.(B and C) A comparison between the UAF1-WDR20-bound USP12 and the Ub-conjugated USP46 structures, focusing on the stabilized PK Loop, the regularized PK Helix, and the F219 residue at the Fingers-Palm domain junction. (D) A close-up view of BL1 and the catalytic cleft of USP12 in complex with UAF1 and WDR20."
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"While the Pinky Finger of USP12 in the UAF1-USP12-WDR20 complex adopts the same b strand conformation as seen in the UAF1-USP12 complex, F219 on the PK Helix becomes embedded in the pocket formed between the Fingers and the Palm domains, instead of being tucked underneath the Fingers domain ( Figures 3D, 5B , and 5C)."
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"WDR20 plays a crucial role in as a " targeting subunit " that modulates CRM1 dependent shuttling of the USP12, UAF1, and WDR20 complex between the plasma membrane, cytoplasm and nucleus."
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"Firstly, we confirm the presence of the Usp12, Uaf-1, and WDR20 complex in PC cells and demonstrate the importance of Uaf-1 and WDR20 for Usp12 stabilisation."
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"Using site directed mutagenesis, we generated a large set of USP12 and WDR20 mutants to characterize in detail the mechanisms and sequence determinants that modulate the subcellular localization of the USP12, UAF1, and WDR20 complex."
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"The accession numbers for the coordinates and structure factors reported in this paper are PDB: 5K16, 5K1B, 5K1A, 5K19, and 5K1C for free USP12, UAF1-USP12 (F222 space group), UAF1-USP12 (C2 space group), WDR20, and UAF1-USP12-WDR20, respectively."
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"olazabal-Herrero et al (88) revealed that Wdr20 facilitates shuttling of the uSP12/uaF1/Wdr20 complex between the plasma membrane, cytoplasm and nucleus via the crM1 pathway, which requires the n-terminal motif of uSP12 and the novel neS of Wdr20.Nucleolin."
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"Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far away from its catalytic center."
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"Overall, the UAF1, USP12, and WDR20 complex is distinguished from the two free USP12 structures and the two UAF1 and USP12 complex structures by the apparent stabilization of most flexible structural elements found in the DUB enzyme."
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"Highlights : Androgen receptor is a key transcriptional regulator in prostate cancer Usp12, Uaf-1, and WDR20 complex plays a crucial role in androgen receptor stability and activity Destabilising an individual Usp12, Uaf-1, and WDR20 complex member reduces the protein levels of the whole complex and diminishes androgen receptor activity Protein levels of all members of the Usp12, Uaf-1, and WDR20 complex are significantly increased in PC INTRODUCTION."
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"A comparison between the activities of the UAF1-USP12 and those of the UAF1, USP12, and WDR20 complex yielded a similar conclusion for WDR20, which also potentiates the enzyme by enhancing its k cat."
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"Overall, the UAF1-USP12-WDR20 complex is distinguished from the two free USP12 structures and the two UAF1-USP12 complex structures by the apparent stabilization of most flexible structural elements found in the DUB."
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"Olazabal-Herrero et al (88) revealed that WDR20 facilitates shuttling of the USP12/UAF1/WDR20 complex between the plasma membrane, cytoplasm and nucleus via the CRM1 pathway, which requires the N-terminal motif of USP12 and the novel NES of WDR20.Nucleolin is a eukaryotic nucleolar phosphoprotein in dense fibrillar regions of the nucleolus, which promotes the synthesis and maturation of ribosomes (7); it also acts as a transcriptional coactivator with chicken ovalbumin upstream promoter transcription factor II and as a membrane receptor for the respiratory syncytial virus (89)."
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"While the Pinky Finger of USP12 in the UAF1, USP12, and WDR20 complex adopts the same beta strand conformation as seen in the UAF1 and USP12 complex, F219 on the PK Helix becomes embedded in the pocke[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"While the Pinky Finger of USP12 in the UAF1, USP12, and WDR20 complex adopts the same beta-strand conformation as seen in the UAF1 and USP12 complex, F219 on the PK Helix becomes embedded in its pocket formed between the Fingers and Palm domains, instead of being tucked underneath the Fingers domain (XREF_FIG, XREF_FIG, XREF_FIG)."
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"Recent structural insights into the USP46 and UAF1 complex and the USP12, UAF1, and WDR20 complex revealed that the activators interact with surfaces remote from the catalytic center and mediate activation via long-range allosteric mechanisms."
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"* Androgen receptor is a key transcriptional regulator in prostate cancer * Usp12, Uaf-1, and WDR20 complex plays a crucial role in androgen receptor stability and activity * Destabilising an individual Usp12, Uaf-1, and WDR20 complex member reduces the protein levels of the whole complex and diminishes androgen receptor activity * Protein levels of all members of the Usp12, Uaf-1, and WDR20 complex are significantly increased in PC."
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"We hypothesise that targeting the Usp12, Uaf-1, and WDR20 complex in a similar manner would allow development of therapeutics with greater specificity and sensitivity than targeting Usp12 alone."
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"Overall, the UAF1, USP12, and WDR20 complex is distinguished from the two free USP12 structures and the two UAF1 and USP12 complex structures by the apparent stabilization of most flexible structural [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Overall these results highlight the potential importance of the Usp12, Uaf-1, and WDR20 complex in AR regulation and PC progression."
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"A comparison between the activities of the UAF1-USP12 and those of the UAF1-USP12-WDR20 complex yielded a similar conclusion for WDR20, which also potentiates the enzyme by enhancing its k cat ."
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