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Structure of USP7 catalytic domain and three Ubl-domains reveals a connector α-helix with regulatory role.

Kim RQ, van Dijk WJ, Sixma TK
J Struct Biol 195 11-8 (2016)
Cited: 25 times
EuropePMC logo PMID: 27183903

Abstract

Ubiquitin conjugation is an important signal in cellular pathways, changing the fate of a target protein, by degradation, relocalisation or complex formation. These signals are balanced by deubiquitinating enzymes (DUBs), which antagonize ubiquitination of specific protein substrates. Because ubiquitination pathways are critically important, DUB activity is often carefully controlled. USP7 is a highly abundant DUB with numerous targets that plays complex roles in diverse pathways, including DNA regulation, p53 stress response and endosomal protein recycling. Full-length USP7 switches between an inactive and an active state, tuned by the positioning of 5 Ubl folds in the C-terminal HUBL domain. The active state requires interaction between the last two Ubls (USP7(45)) and the catalytic domain (USP7(CD)), and this can be promoted by allosteric interaction from the first 3 Ubl domains of USP7 (USP7(123)) interacting with GMPS. Here we study the transition between USP7 states. We provide a crystal structure of USP7(CD123) and show that CD and Ubl123 are connected via an extended charged alpha helix. Mutational analysis is used to determine whether the charge and rigidity of this 'connector helix' are important for full USP7 activity.

Reviews - 5fwi mentioned but not cited (3)

  1. USP7: Structure, substrate specificity, and inhibition. Pozhidaeva A, Bezsonova I. DNA Repair (Amst) 76 30-39 (2019)
  2. USP7 Is a Master Regulator of Genome Stability. Valles GJ, Bezsonova I, Woodgate R, Ashton NW, Ashton NW. Front Cell Dev Biol 8 717 (2020)
  3. Molecular Mechanisms of DUBs Regulation in Signaling and Disease. Li Y, Reverter D. Int J Mol Sci 22 986 (2021)

Articles - 5fwi mentioned but not cited (4)

  1. Emerging insights into HAUSP (USP7) in physiology, cancer and other diseases. Bhattacharya S, Chakraborty D, Basu M, Ghosh MK. Signal Transduct Target Ther 3 17 (2018)
  2. USP7: Novel Drug Target in Cancer Therapy. Wang Z, Kang W, You Y, Pang J, Ren H, Suo Z, Liu H, Zheng Y. Front Pharmacol 10 427 (2019)
  3. Molecular dynamics simulation reveals the possible druggable hot-spots of USP7. Srivastava M, Suri C, Singh M, Mathur R, Asthana S. Oncotarget 9 34289-34305 (2018)
  4. Neuroinflammation inhibition by small-molecule targeting USP7 noncatalytic domain for neurodegenerative disease therapy. Zhang XW, Feng N, Liu YC, Guo Q, Wang JK, Bai YZ, Ye XM, Yang Z, Yang H, Liu Y, Yang MM, Wang YH, Shi XM, Liu D, Tu PF, Zeng KW. Sci Adv 8 eabo0789 (2022)


Reviews citing this publication (7)

  1. Mechanisms of Deubiquitinase Specificity and Regulation. Mevissen TET, Komander D. Annu Rev Biochem 86 159-192 (2017)
  2. Modulation of the p53/MDM2 interplay by HAUSP inhibitors. Tavana O, Gu W. J Mol Cell Biol 9 45-52 (2017)
  3. Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet? Qi SM, Cheng G, Cheng XD, Xu Z, Xu B, Zhang WD, Qin JJ. Front Cell Dev Biol 8 233 (2020)
  4. USP7 Inhibitors in Cancer Immunotherapy: Current Status and Perspective. Korenev G, Yakukhnov S, Druk A, Golovina A, Chasov V, Mirgayazova R, Ivanov R, Bulatov E. Cancers (Basel) 14 5539 (2022)
  5. The emerging role of Deubiquitinases (DUBs) in parasites: A foresight review. Kumar P, Kumar P, Mandal D, Velayutham R. Front Cell Infect Microbiol 12 985178 (2022)
  6. Targeted therapy based on ubiquitin-specific proteases, signalling pathways and E3 ligases in non-small-cell lung cancer. Yang YC, Zhao CJ, Jin ZF, Zheng J, Ma LT. Front Oncol 13 1120828 (2023)
  7. Targeting ubiquitin specific proteases (USPs) in cancer immunotherapy: from basic research to preclinical application. Gao H, Yin J, Ji C, Yu X, Xue J, Guan X, Zhang S, Liu X, Xing F. J Exp Clin Cancer Res 42 225 (2023)

Articles citing this publication (11)

  1. Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Turnbull AP, Ioannidis S, Krajewski WW, Pinto-Fernandez A, Heride C, Martin ACL, Tonkin LM, Townsend EC, Buker SM, Lancia DR, Caravella JA, Toms AV, Charlton TM, Lahdenranta J, Wilker E, Follows BC, Evans NJ, Stead L, Alli C, Zarayskiy VV, Talbot AC, Buckmelter AJ, Wang M, McKinnon CL, Saab F, McGouran JF, Century H, Gersch M, Pittman MS, Marshall CG, Raynham TM, Simcox M, Stewart LMD, McLoughlin SB, Escobedo JA, Bair KW, Dinsmore CJ, Hammonds TR, Kim S, Urbé S, Clague MJ, Kessler BM, Komander D. Nature 550 481-486 (2017)
  2. AI revolutions in biology: The joys and perils of AlphaFold. Perrakis A, Sixma TK. EMBO Rep 22 e54046 (2021)
  3. Dual-utility NLS drives RNF169-dependent DNA damage responses. An L, Jiang Y, Ng HH, Man EP, Chen J, Khoo US, Gong Q, Huen MS. Proc Natl Acad Sci U S A 114 E2872-E2881 (2017)
  4. Ubiquitin-specific protease 7 is a drug-able target that promotes hepatocellular carcinoma and chemoresistance. Zhang W, Zhang J, Xu C, Zhang S, Bian S, Jiang F, Ni W, Qu L, Lu C, Ni R, Fan Y, Xiao M, Liu J. Cancer Cell Int 20 28 (2020)
  5. The Ubiquitin-Specific Protease Usp7, a Novel Merkel Cell Polyomavirus Large T-Antigen Interaction Partner, Modulates Viral DNA Replication. Czech-Sioli M, Siebels S, Radau S, Zahedi RP, Schmidt C, Dobner T, Grundhoff A, Fischer N. J Virol 94 e01638-19 (2020)
  6. Kinetic analysis of multistep USP7 mechanism shows critical role for target protein in activity. Kim RQ, Geurink PP, Mulder MPC, Fish A, Ekkebus R, El Oualid F, van Dijk WJ, van Dalen D, Ovaa H, van Ingen H, Sixma TK. Nat Commun 10 231 (2019)
  7. Preferential digestion of PCNA-ubiquitin and p53-ubiquitin linkages by USP7 to remove polyubiquitin chains from substrates. Masuda Y, Kanao R, Kawai H, Kukimoto I, Masutani C. J Biol Chem 294 4177-4187 (2019)
  8. Panel of Engineered Ubiquitin Variants Targeting the Family of Human Ubiquitin Interacting Motifs. Veggiani G, Yates BP, Martyn GD, Manczyk N, Singer AU, Kurinov I, Sicheri F, Sidhu SS. ACS Chem Biol 17 941-956 (2022)
  9. Deubiquitination of BES1 by UBP12/UBP13 promotes brassinosteroid signaling and plant growth. Park SH, Jeong JS, Zhou Y, Binte Mustafa NF, Chua NH. Plant Commun 3 100348 (2022)
  10. The role of USP7 in the Shoc2-ERK1/2 signaling axis and Noonan-like syndrome with loose anagen hair. Wilson P, Abdelmoti L, Norcross R, Jang ER, Palayam M, Galperin E. J Cell Sci 134 jcs258922 (2021)
  11. Backbone and ILV side-chain NMR resonance assignments of the catalytic domain of human deubiquitinating enzyme USP7. Valles G, Pozhidaeva A, Korzhnev DM, Bezsonova I. Biomol NMR Assign 16 197-203 (2022)


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