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Structural basis of the activation and degradation mechanisms of the E3 ubiquitin ligase Nedd4L.

Escobedo A, Gomes T, Aragón E, Martín-Malpartida P, Ruiz L, Macias MJ
Structure 22 1446-57 (2014)
Cited: 41 times
EuropePMC logo PMID: 25295397

Abstract

We investigated the mechanisms of activation and degradation of the E3 ubiquitin ligase Nedd4L combining the available biochemical information with complementary biophysical techniques. Using nuclear magnetic resonance spectroscopy, we identified that the C2 domain binds Ca(2+) and inositol 1,4,5-trisphosphate (IP3) using the same interface that is used to interact with the HECT domain. Thus, we propose that the transition from the closed to the active form is regulated by a competition of IP3 and Ca(2+) with the HECT domain for binding to the C2 domain. We performed relaxation experiments and molecular dynamic simulations to determine the flexibility of the HECT structure and observed that its conserved PY motif can become solvent-exposed when the unfolding process is initiated. The structure of the WW3 domain bound to the HECT-PY site reveals the details of this interaction, suggesting a possible auto-ubquitination mechanism using two molecules, a partially unfolded one and a fully functional Nedd4L counterpart.

Articles - 2mpt mentioned but not cited (2)

  1. Interactions between AMOT PPxY motifs and NEDD4L WW domains function in HIV-1 release. Rheinemann L, Thompson T, Mercenne G, Paine EL, Peterson FC, Volkman BF, Alam SL, Alian A, Sundquist WI. J Biol Chem 297 100975 (2021)
  2. U24 from Roseolovirus interacts strongly with Nedd4 WW Domains. Sang Y, Zhang R, Scott WR, Creagh AL, Haynes CA, Straus SK. Sci Rep 7 39776 (2017)


Reviews citing this publication (12)

  1. Regulating the Regulators: Recent Revelations in the Control of E3 Ubiquitin Ligases. Vittal V, Stewart MD, Brzovic PS, Klevit RE. J. Biol. Chem. 290 21244-21251 (2015)
  2. Targeting HECT-type E3 ligases - insights from catalysis, regulation and inhibitors. Fajner V, Maspero E, Polo S. FEBS Lett. 591 2636-2647 (2017)
  3. Structural mechanisms of HECT-type ubiquitin ligases. Lorenz S. Biol. Chem. 399 127-145 (2018)
  4. Developing Small-Molecule Inhibitors of HECT-Type Ubiquitin Ligases for Therapeutic Applications: Challenges and Opportunities. Chen D, Gehringer M, Lorenz S. Chembiochem 19 2123-2135 (2018)
  5. Regulating the human HECT E3 ligases. Sluimer J, Distel B. Cell. Mol. Life Sci. 75 3121-3141 (2018)
  6. Adaptors as the regulators of HECT ubiquitin ligases. Shah SS, Kumar S. Cell Death Differ 28 455-472 (2021)
  7. Calcium, an Emerging Intracellular Messenger for the Hippo Pathway Regulation. Wei Y, Li W. Front Cell Dev Biol 9 694828 (2021)
  8. Genetic analysis of periventricular nodular heterotopia 7 caused by a novel NEDD4L missense mutation: Case and literature summary. Liu J, Hu J, Duan Y, Qin R, Guo C, Zhou H, Liu H, Liu C. Mol Genet Genomic Med 11 e2169 (2023)
  9. The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease. Goto J, Otaki Y, Watanabe T, Watanabe M. Int J Mol Sci 22 6065 (2021)
  10. The Role of NEDD4 E3 Ubiquitin-Protein Ligases in Parkinson's Disease. Conway JA, Kinsman G, Kramer ER. Genes (Basel) 13 513 (2022)
  11. The many substrates and functions of NEDD4-1. Huang X, Chen J, Cao W, Yang L, Chen Q, He J, Yi Q, Huang H, Zhang E, Cai Z. Cell Death Dis 10 904 (2019)
  12. Ubiquitination as a Key Regulator of Endosomal Signaling by GPCRs. Burton JC, Grimsey NJ. Front Cell Dev Biol 7 43 (2019)

Articles citing this publication (27)

  1. System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes. Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J, Rotin D, Schulman BA, Sidhu SS. Mol. Cell 62 121-136 (2016)
  2. Itch WW Domains Inhibit Its E3 Ubiquitin Ligase Activity by Blocking E2-E3 Ligase Trans-thiolation. Riling C, Kamadurai H, Kumar S, O'Leary CE, Wu KP, Manion EE, Ying M, Schulman BA, Oliver PM. J. Biol. Chem. 290 23875-23887 (2015)
  3. A Tunable Brake for HECT Ubiquitin Ligases. Chen Z, Jiang H, Xu W, Li X, Dempsey DR, Zhang X, Devreotes P, Wolberger C, Amzel LM, Gabelli SB, Cole PA. Mol. Cell 66 345-357.e6 (2017)
  4. Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia. Broix L, Jagline H, Ivanova E, Schmucker S, Drouot N, Clayton-Smith J, Pagnamenta AT, Metcalfe KA, Isidor B, Louvier UW, Poduri A, Taylor JC, Tilly P, Poirier K, Saillour Y, Lebrun N, Stemmelen T, Rudolf G, Muraca G, Saintpierre B, Elmorjani A, Deciphering Developmental Disorders study, Moïse M, Weirauch NB, Guerrini R, Boland A, Olaso R, Masson C, Tripathy R, Keays D, Beldjord C, Nguyen L, Godin J, Kini U, Nischké P, Deleuze JF, Bahi-Buisson N, Sumara I, Hinckelmann MV, Chelly J. Nat. Genet. 48 1349-1358 (2016)
  5. STK35 Is Ubiquitinated by NEDD4L and Promotes Glycolysis and Inhibits Apoptosis Through Regulating the AKT Signaling Pathway, Influencing Chemoresistance of Colorectal Cancer. Yang H, Zhu J, Wang G, Liu H, Zhou Y, Qian J. Front Cell Dev Biol 8 582695 (2020)
  6. Allosteric auto-inhibition and activation of the Nedd4 family E3 ligase Itch. Zhu K, Shan Z, Chen X, Cai Y, Cui L, Yao W, Wang Z, Shi P, Tian C, Lou J, Xie Y, Wen W. EMBO Rep. 18 1618-1630 (2017)
  7. A conformational switch regulates the ubiquitin ligase HUWE1. Sander B, Xu W, Eilers M, Popov N, Lorenz S. Elife 6 (2017)
  8. The E3 Ubiquitin Ligase NEDD4L Targets OGG1 for Ubiquitylation and Modulates the Cellular DNA Damage Response. Hughes JR, Parsons JL. Front Cell Dev Biol 8 607060 (2020)
  9. E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Gao P, Ma X, Yuan M, Yi Y, Liu G, Wen M, Jiang W, Ji R, Zhu L, Tang Z, Yu Q, Xu J, Yang R, Xia S, Yang M, Pan J, Yuan H, An H. Nat Commun 12 1194 (2021)
  10. NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling. Wang Z, Dang T, Liu T, Chen S, Li L, Huang S, Fang M. J. Biol. Chem. 291 17467-17477 (2016)
  11. The mechanism of neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2)/NEDD4L-catalyzed polyubiquitin chain assembly. Todaro DR, Augustus-Wallace AC, Klein JM, Haas AL. J. Biol. Chem. 292 19521-19536 (2017)
  12. Ehrlichia chaffeensis TRP120 Moonlights as a HECT E3 Ligase Involved in Self- and Host Ubiquitination To Influence Protein Interactions and Stability for Intracellular Survival. Zhu B, Das S, Mitra S, Farris TR, McBride JW. Infect. Immun. 85 (2017)
  13. 14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains. Pohl P, Joshi R, Petrvalska O, Obsil T, Obsilova V. Commun Biol 4 899 (2021)
  14. Substrate clustering potently regulates the activity of WW-HECT domain-containing ubiquitin ligases. Mund T, Pelham HR. J. Biol. Chem. 293 5200-5209 (2018)
  15. A Tyrosine Switch on NEDD4-2 E3 Ligase Transmits GPCR Inflammatory Signaling. Grimsey NJ, Narala R, Rada CC, Mehta S, Stephens BS, Kufareva I, Lapek J, Gonzalez DJ, Handel TM, Zhang J, Trejo J. Cell Rep 24 3312-3323.e5 (2018)
  16. WW domain-mediated regulation and activation of E3 ubiquitin ligase Suppressor of Deltex. Yao W, Shan Z, Gu A, Fu M, Shi Z, Wen W. J. Biol. Chem. 293 16697-16708 (2018)
  17. Interactions of U24 from Roseolovirus with WW domains: canonical vs noncanonical. Sang Y, Zhang R, Creagh AL, Haynes CA, Straus SK. Biochem. Cell Biol. 95 350-358 (2017)
  18. A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases. Wang Z, Liu Z, Chen X, Li J, Yao W, Huang S, Gu A, Lei QY, Mao Y, Wen W. Nat Commun 10 3162 (2019)
  19. Boolean model of growth signaling, cell cycle and apoptosis predicts the molecular mechanism of aberrant cell cycle progression driven by hyperactive PI3K. Sizek H, Hamel A, Deritei D, Campbell S, Ravasz Regan E. PLoS Comput. Biol. 15 e1006402 (2019)
  20. Drug-induced lactate confers ferroptosis resistance via p38-SGK1-NEDD4L-dependent upregulation of GPX4 in NSCLC cells. Cheng F, Dou J, Yang Y, Sun S, Chen R, Zhang Z, Wei H, Li J, Wu Z. Cell Death Discov 9 165 (2023)
  21. Elevated intracellular Na+ and osmolarity stimulate catalytic activity of the ubiquitin ligase Nedd4-2. Persaud A, Jiang C, Liu Z, Kefalas G, Demian WL, Rotin D. Proc Natl Acad Sci U S A 119 e2122495119 (2022)
  22. Familial NEDD4L variant in periventricular nodular heterotopia and in a fetus with hypokinesia and flexion contractures. Elbracht M, Kraft F, Begemann M, Holschbach P, Mull M, Kabat IM, Müller B, Häusler M, Kurth I, Hehr U. Mol Genet Genomic Med 6 1255-1260 (2018)
  23. Predicting PY motif-mediated protein-protein interactions in the Nedd4 family of ubiquitin ligases. Hatstat AK, Pupi MD, McCafferty DG. PLoS One 16 e0258315 (2021)
  24. Primate-specific isoform of Nedd4-1 regulates substrate binding via Ser/Thr phosphorylation and 14-3-3 binding. Kefalas G, Rotin D. Sci Rep 13 17903 (2023)
  25. Robust and facile purification of full-length, untagged human Nedd4 as a recombinant protein from Escherichia coli. Hatstat AK, McCafferty DG. Protein Expr Purif 173 105649 (2020)
  26. The Dual Regulation Effects of ESR1/NEDD4L on SLC7A11 in Breast Cancer Under Ionizing Radiation. Liu R, Liu L, Bian Y, Zhang S, Wang Y, Chen H, Jiang X, Li G, Chen Q, Xue C, Li M, Liu L, Liu X, Ma S. Front Cell Dev Biol 9 772380 (2021)
  27. Tril dampens Nodal signaling through Pellino2- and Traf6-mediated activation of Nedd4l. Kim HS, Green YS, Xie Y, Christian JL. Proc Natl Acad Sci U S A 118 e2104661118 (2021)


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