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Structural Insights into WD-Repeat 48 Activation of Ubiquitin-Specific Protease 46.

Yin J, Schoeffler AJ, Wickliffe K, Newton K, Starovasnik MA, Dueber EC, Harris SF
Structure 23 2043-54 (2015)
Related entries: 5cvl, 5cvn, 5cvo

Cited: 39 times
EuropePMC logo PMID: 26388029

Abstract

Protein ubiquitination patterns are an important component of cellular signaling. The WD-repeat protein WDR48 (USP1-associated factor UAF-1) stimulates activity of ubiquitin-specific proteases USP1, USP12, and USP46. To understand how WDR48 exerts its effect on the USP scaffold, we determined structures of the ternary WDR48:USP46:ubiquitin complex. WDR48 interacts with the USP46 fingers subdomain via a relatively small, highly polar surface on the top center of the WDR48 β propeller. In addition, WDR48 has a novel ancillary domain and a C-terminal SUMO-like domain encircling the USP46-bound ubiquitin. Mutation of residues involved in the WDR48:USP46 interaction abrogated both binding and deubiquitinase activity of the complex. An analogous mutation in USP1 similarly blocked WDR48-dependent activation. Our data suggest a possible mechanism of deubiquitinase stimulation via stabilization and prolonged residence time of substrate. The unprecedented mode of interaction between the USP fingers domain and the WD-repeat β propeller serves as a prototypical example for this family of deubiquitinases.

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  2. USP44 Is an Integral Component of N-CoR that Contributes to Gene Repression by Deubiquitinating Histone H2B. Lan X, Atanassov BS, Li W, Zhang Y, Florens L, Mohan RD, Galardy PJ, Washburn MP, Workman JL, Dent SYR. Cell Rep 17 2382-2393 (2016)
  3. WDR79 mediates the proliferation of non-small cell lung cancer cells by regulating the stability of UHRF1. Chen J, Sheng X, Ma H, Tang Z, Yang C, Cao L, Sun Y, Deng T, Feng P, Hu B, Wei D, Liu J, Xiong W, Ye M. J. Cell. Mol. Med. 22 2856-2864 (2018)
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  5. USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors. Lim KS, Li H, Roberts EA, Gaudiano EF, Clairmont C, Sambel LA, Ponnienselvan K, Liu JC, Yang C, Kozono D, Parmar K, Yusufzai T, Zheng N, D'Andrea AD. Mol. Cell 72 925-941.e4 (2018)
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  9. Characterization of the deubiquitination activity and substrate specificity of the chicken ubiquitin-specific protease 1/USP associated factor 1 complex. Zheng H, Wang M, Zhao C, Wu S, Yu P, Lü Y, Wang T, Ai Y. PLoS ONE 12 e0186535 (2017)
  10. Destructive twisting of neutral metalloproteases: the catalysis mechanism of the Dispase autolysis-inducing protein from Streptomyces mobaraensis DSM 40487. Fiebig D, Storka J, Roeder M, Meyners C, Schmelz S, Blankenfeldt W, Scrima A, Kolmar H, Fuchsbauer HL. FEBS J. 285 4246-4264 (2018)
  11. Divergence in Ubiquitin Interaction and Catalysis among the Ubiquitin-Specific Protease Family Deubiquitinating Enzymes. Tencer AH, Liang Q, Zhuang Z. Biochemistry 55 4708-4719 (2016)
  12. Insert L1 is a central hub for allosteric regulation of USP1 activity. Dharadhar S, van Dijk WJ, Scheffers S, Fish A, Sixma TK. EMBO Rep 22 e51749 (2021)
  13. Myosin Va interacts with the exosomal protein spermine synthase. Dolce LG, Silva-Junior RMP, Assis LHP, Nascimento AFZ, Araujo JS, Meschede IP, Espreafico EM, de Giuseppe PO, Murakami MT. Biosci. Rep. 39 (2019)
  14. The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling. Ng VH, Spencer Z, Neitzel LR, Nayak A, Loberg MA, Shen C, Kassel SN, Kroh HK, An Z, Anthony CC, Bryant JM, Lawson A, Goldsmith L, Benchabane H, Hansen AG, Li J, D'Souza S, Lebensohn AM, Rohatgi R, Weiss WA, Weiss VL, Williams C, Hong CC, Robbins DJ, Ahmed Y, Lee E. Nat Commun 14 6173 (2023)
  15. The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6. Spencer ZT, Ng VH, Benchabane H, Siddiqui GS, Duwadi D, Maines B, Bryant JM, Schwarzkopf A, Yuan K, Kassel SN, Mishra A, Pimentel A, Lebensohn AM, Rohatgi R, Gerber SA, Robbins DJ, Lee E, Ahmed Y. Nat Commun 14 6174 (2023)
  16. The novel anti-androgen candidate galeterone targets deubiquitinating enzymes, USP12 and USP46, to control prostate cancer growth and survival. McClurg UL, Azizyan M, Dransfield DT, Namdev N, Chit NCTH, Nakjang S, Robson CN. Oncotarget 9 24992-25007 (2018)
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  21. HPVE6-USP46 Mediated Cdt2 Stabilization Reduces Set8 Mediated H4K20-Methylation to Induce Gene Expression Changes. Kiran S, Wilson B, Saha S, Graff JA, Dutta A. Cancers (Basel) 14 30 (2021)
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  27. The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel. Ward SJ, Gratton HE, Indrayudha P, Michavila C, Mukhopadhyay R, Maurer SK, Caulton SG, Emsley J, Dreveny I. J. Biol. Chem. 293 17362-17374 (2018)
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