5k1c
Crystal structure of the UAF1/WDR20/USP12 complexCrystal structure of the UAF1/WDR20/USP12 complex
Structural highlights
Disease[WDR48_HUMAN] Autosomal recessive spastic paraplegia type 60. Function[UBP12_HUMAN] Deubiquitinating enzyme. Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity. Not involved in deubiquitination of monoubiquitinated FANCD2.[1] [WDR48_HUMAN] Regulator of deubiquitinating complexes. Acts as a strong activator of USP1 by enhancing the USP1-mediated deubiquitination of FANCD2; USP1 being almost inactive by itself. Also activates deubiquitinating activity of complexes containing USP12 and USP46, respectively. Activates deubiquitination by increasing the catalytic turnover without increasing the affinity of deubiquitinating enzymes for the substrate. In case of infection by Herpesvirus saimiri, may play a role in vesicular transport or membrane fusion events necessary for transport to lysosomes. Induces lysosomal vesicle formation via interaction with Herpesvirus saimiri tyrosine kinase-interacting protein (TIP). Subsequently, TIP recruits tyrosine-protein kinase LCK, resulting in down-regulation of T-cell antigen receptor TCR. May play a role in generation of enlarged endosomal vesicles via interaction with TIP. In case of infection by papillomavirus HPV11, promotes the maintenance of the viral genome via its interaction with HPV11 helicase E1.[2] [3] [4] Publication Abstract from PubMedUbiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two beta-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two beta-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners. Allosteric Activation of Ubiquitin-Specific Proteases by beta-Propeller Proteins UAF1 and WDR20.,Li H, Lim KS, Kim H, Hinds TR, Jo U, Mao H, Weller CE, Sun J, Chatterjee C, D'Andrea AD, Zheng N Mol Cell. 2016 Jul 21;63(2):249-60. doi: 10.1016/j.molcel.2016.05.031. Epub 2016 , Jun 30. PMID:27373336[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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