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An invisible ubiquitin conformation is required for efficient phosphorylation by PINK1.

Gladkova C, Schubert AF, Wagstaff JL, Pruneda JN, Freund SM, Komander D
EMBO J 36 3555-3572 (2017)
Cited: 29 times
EuropePMC logo PMID: 29133469

Abstract

The Ser/Thr protein kinase PINK1 phosphorylates the well-folded, globular protein ubiquitin (Ub) at a relatively protected site, Ser65. We previously showed that Ser65 phosphorylation results in a conformational change in which Ub adopts a dynamic equilibrium between the known, common Ub conformation and a distinct, second conformation wherein the last β-strand is retracted to extend the Ser65 loop and shorten the C-terminal tail. We show using chemical exchange saturation transfer (CEST) nuclear magnetic resonance experiments that a similar, C-terminally retracted (Ub-CR) conformation also exists at low population in wild-type Ub. Point mutations in the moving β5 and neighbouring β-strands shift the Ub/Ub-CR equilibrium. This enabled functional studies of the two states, and we show that while the Ub-CR conformation is defective for conjugation, it demonstrates improved binding to PINK1 through its extended Ser65 loop, and is a superior PINK1 substrate. Together our data suggest that PINK1 utilises a lowly populated yet more suitable Ub-CR conformation of Ub for efficient phosphorylation. Our findings could be relevant for many kinases that phosphorylate residues in folded protein domains.

Articles - 5oxh mentioned but not cited (2)

  1. Structure of PINK1 in complex with its substrate ubiquitin. Schubert AF, Gladkova C, Pardon E, Wagstaff JL, Freund SMV, Steyaert J, Maslen SL, Komander D. Nature 552 51-56 (2017)
  2. An invisible ubiquitin conformation is required for efficient phosphorylation by PINK1. Gladkova C, Schubert AF, Wagstaff JL, Pruneda JN, Freund SM, Komander D. EMBO J 36 3555-3572 (2017)


Reviews citing this publication (6)

  1. Building and decoding ubiquitin chains for mitophagy. Harper JW, Ordureau A, Heo JM. Nat Rev Mol Cell Biol 19 93-108 (2018)
  2. An expanded lexicon for the ubiquitin code. Dikic I, Schulman BA. Nat Rev Mol Cell Biol 24 273-287 (2023)
  3. New insights into the structure of PINK1 and the mechanism of ubiquitin phosphorylation. Rasool S, Trempe JF. Crit Rev Biochem Mol Biol 53 515-534 (2018)
  4. Quo Vadis Biomolecular NMR Spectroscopy? Selenko P. Int J Mol Sci 20 E1278 (2019)
  5. The Role of Conformational Dynamics in the Recognition and Regulation of Ubiquitination. Khago D, Fucci IJ, Byrd RA. Molecules 25 E5933 (2020)
  6. On the necessity of an integrative approach to understand protein structural dynamics. Yang QF, Tang C. J Zhejiang Univ Sci B 20 496-502 (2019)

Articles citing this publication (21)

  1. Mechanism of parkin activation by PINK1. Gladkova C, Maslen SL, Skehel JM, Komander D. Nature 559 410-414 (2018)
  2. PINK1 autophosphorylation is required for ubiquitin recognition. Rasool S, Soya N, Truong L, Croteau N, Lukacs GL, Trempe JF. EMBO Rep 19 e44981 (2018)
  3. Activation mechanism of PINK1. Gan ZY, Callegari S, Cobbold SA, Cotton TR, Mlodzianoski MJ, Schubert AF, Geoghegan ND, Rogers KL, Leis A, Dewson G, Glukhova A, Komander D. Nature 602 328-335 (2022)
  4. Sensitive ELISA-based detection method for the mitophagy marker p-S65-Ub in human cells, autopsy brain, and blood samples. Watzlawik JO, Hou X, Fricova D, Ramnarine C, Barodia SK, Gendron TF, Heckman MG, DeTure M, Siuda J, Wszolek ZK, Scherzer CR, Ross OA, Bu G, Dickson DW, Goldberg MS, Fiesel FC, Springer W. Autophagy 17 2613-2628 (2021)
  5. Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA. Rennie ML, Lemonidis K, Arkinson C, Chaugule VK, Clarke M, Streetley J, Spagnolo L, Walden H. EMBO Rep 21 e50133 (2020)
  6. Structural insights into ubiquitin phosphorylation by PINK1. Okatsu K, Sato Y, Yamano K, Matsuda N, Negishi L, Takahashi A, Yamagata A, Goto-Ito S, Mishima M, Ito Y, Oka T, Tanaka K, Fukai S. Sci Rep 8 10382 (2018)
  7. High-Resolution NMR of Folded Proteins in Hyperpolarized Physiological Solvents. Kadeřávek P, Ferrage F, Bodenhausen G, Kurzbach D. Chemistry 24 13418-13423 (2018)
  8. Structural basis for feedforward control in the PINK1/Parkin pathway. Sauvé V, Sung G, MacDougall EJ, Kozlov G, Saran A, Fakih R, Fon EA, Gehring K. EMBO J 41 e109460 (2022)
  9. Observation and Kinetic Characterization of Transient Schiff Base Intermediates by CEST NMR Spectroscopy. Ramanujam V, Charlier C, Bax A. Angew Chem Int Ed Engl 58 15309-15312 (2019)
  10. Structural and functional consequences of NEDD8 phosphorylation. Stuber K, Schneider T, Werner J, Kovermann M, Marx A, Scheffner M. Nat Commun 12 5939 (2021)
  11. Synthesis and delivery of a stable phosphorylated ubiquitin probe to study ubiquitin conjugation in mitophagy. Mann G, Satish G, Sulkshane P, Mandal S, Glickman MH, Brik A. Chem Commun (Camb) 57 9438-9441 (2021)
  12. Multiple frequency saturation pulses reduce CEST acquisition time for quantifying conformational exchange in biomolecules. Leninger M, Marsiglia WM, Jerschow A, Traaseth NJ. J Biomol NMR 71 19-30 (2018)
  13. Exchangeable deuterons introduce artifacts in amide 15N CEST experiments used to study protein conformational exchange. Tiwari VP, Pandit S, Vallurupalli P. J Biomol NMR 73 43-48 (2019)
  14. Identification and Characterization of Mutations in Ubiquitin Required for Non-covalent Dimer Formation. Gabrielsen M, Buetow L, Kowalczyk D, Zhang W, Sidhu SS, Huang DT. Structure 27 1452-1459.e4 (2019)
  15. Measuring the signs of the methyl 1H chemical shift differences between major and 'invisible' minor protein conformational states using methyl 1H multi-quantum spectroscopy. Gopalan AB, Vallurupalli P. J Biomol NMR 70 187-202 (2018)
  16. Substitution of PINK1 Gly411 modulates substrate receptivity and turnover. Fiesel FC, Fričová D, Hayes CS, Coban MA, Hudec R, Bredenberg JM, Broadway BJ, Markham BN, Yan T, Boneski PK, Fiorino G, Watzlawik JO, Hou X, McCarty AM, Lewis-Tuffin LJ, Zhong J, Madden BJ, Ordureau A, An H, Puschmann A, Wszolek ZK, Ross OA, Harper JW, Caulfield TR, Springer W. Autophagy 19 1711-1732 (2023)
  17. A high-field cellular DNP-supported solid-state NMR approach to study proteins with sub-cellular specificity. Beriashvili D, Yao R, D'Amico F, Krafčíková M, Gurinov A, Safeer A, Cai X, Mulder MPC, Liu Y, Folkers GE, Baldus M. Chem Sci 14 9892-9899 (2023)
  18. Enhancing Biomolecular Simulations with Hybrid Potentials Incorporating NMR Data. Qi G, Vrettas MD, Biancaniello C, Sanz-Hernandez M, Cafolla CT, Morgan JWR, Wang Y, De Simone A, Wales DJ. J Chem Theory Comput 18 7733-7750 (2022)
  19. The A39G FF domain folds on a volcano-shaped free energy surface via separate pathways. Tiwari VP, Toyama Y, De D, Kay LE, Vallurupalli P. Proc Natl Acad Sci U S A 118 e2115113118 (2021)
  20. Letter Ubiquitin is double-phosphorylated by PINK1 for enhanced pH-sensitivity of conformational switch. Ye SX, Gong Z, Yang J, An YX, Liu Z, Zhao Q, Lescop E, Dong X, Tang C. Protein Cell 10 908-913 (2019)
  21. Phosphorylation at Ser65 modulates ubiquitin conformational dynamics. Yovanno RA, Yu A, Wied TJ, Lau AY. Structure 31 884-890.e2 (2023)


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