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Crystal structure of the human ubiquitin-activating enzyme 5 (UBA5) bound to ATP: mechanistic insights into a minimalistic E1 enzyme.

Bacik JP, Walker JR, Ali M, Schimmer AD, Dhe-Paganon S
J Biol Chem 285 20273-80 (2010)
Cited: 42 times
EuropePMC logo PMID: 20368332

Abstract

E1 ubiquitin-activating enzymes (UBAs) are large multidomain proteins that catalyze formation of a thioester bond between the terminal carboxylate of a ubiquitin or ubiquitin-like modifier (UBL) and a conserved cysteine in an E2 protein, producing reactive ubiquityl units for subsequent ligation to substrate lysines. Two important E1 reaction intermediates have been identified: a ubiquityl-adenylate phosphoester and a ubiquityl-enzyme thioester. However, the mechanism of thioester bond formation and its subsequent transfer to an E2 enzyme remains poorly understood. We have determined the crystal structure of the human UFM1 (ubiquitin-fold modifier 1) E1-activating enzyme UBA5, bound to ATP, revealing a structure that shares similarities with both large canonical E1 enzymes and smaller ancestral E1-like enzymes. In contrast to other E1 active site cysteines, which are in a variably sized domain that is separate and flexible relative to the adenylation domain, the catalytic cysteine of UBA5 (Cys(250)) is part of the adenylation domain in an alpha-helical motif. The novel position of the UBA5 catalytic cysteine and conformational changes associated with ATP binding provides insight into the possible mechanisms through which the ubiquityl-enzyme thioester is formed. These studies reveal structural features that further our understanding of the UBA5 enzyme reaction mechanism and provide insight into the evolution of ubiquitin activation.

Articles - 3h8v mentioned but not cited (8)

  1. Predicting new indications for approved drugs using a proteochemometric method. Dakshanamurthy S, Issa NT, Assefnia S, Seshasayee A, Peters OJ, Madhavan S, Uren A, Brown ML, Byers SW. J Med Chem 55 6832-6848 (2012)
  2. Crystal structure of the human ubiquitin-activating enzyme 5 (UBA5) bound to ATP: mechanistic insights into a minimalistic E1 enzyme. Bacik JP, Walker JR, Ali M, Schimmer AD, Dhe-Paganon S. J Biol Chem 285 20273-20280 (2010)
  3. Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence. Padala P, Oweis W, Mashahreh B, Soudah N, Cohen-Kfir E, Todd EA, Berndsen CE, Wiener R. Sci Rep 7 508 (2017)
  4. Characterization, crystallization and preliminary X-ray crystallographic analysis of the human Uba5 C-terminus-Ufc1 complex. Xie S. Acta Crystallogr F Struct Biol Commun 70 1093-1097 (2014)
  5. Distinct Conformation of ATP Molecule in Solution and on Protein. Kobayashi E, Yura K, Nagai Y. Biophysics (Nagoya-shi) 9 1-12 (2013)
  6. The crystal structure and small-angle X-ray analysis of CsdL/TcdA reveal a new tRNA binding motif in the MoeB/E1 superfamily. López-Estepa M, Ardá A, Savko M, Round A, Shepard WE, Bruix M, Coll M, Fernández FJ, Jiménez-Barbero J, Vega MC. PLoS One 10 e0118606 (2015)
  7. Characterization, crystallization and preliminary X-ray crystallographic analysis of the Uba5 fragment necessary for high-efficiency activation of Ufm1. Xie S. Acta Crystallogr F Struct Biol Commun 70 765-768 (2014)
  8. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)


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  1. Ubiquitin-like Protein Conjugation: Structures, Chemistry, and Mechanism. Cappadocia L, Lima CD. Chem Rev 118 889-918 (2018)
  2. The UFMylation System in Proteostasis and Beyond. Gerakis Y, Quintero M, Li H, Hetz C. Trends Cell Biol 29 974-986 (2019)
  3. UFMylation: A Unique & Fashionable Modification for Life. Wei Y, Xu X. Genomics Proteomics Bioinformatics 14 140-146 (2016)
  4. Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives. Andreoli F, Barbosa AJ, Parenti MD, Del Rio A. Curr Pharm Des 19 578-613 (2013)
  5. Ubiquitin-like modifications in the DNA damage response. Wang Z, Zhu WG, Xu X. Mutat Res 803-805 56-75 (2017)
  6. Decrypting UFMylation: How Proteins Are Modified with UFM1. Banerjee S, Kumar M, Wiener R. Biomolecules 10 E1442 (2020)
  7. Ubiquitin-fold modifier 1 acts as a positive regulator of breast cancer. Yoo HM, Park JH, Jeon YJ, Chung CH. Front Endocrinol (Lausanne) 6 36 (2015)
  8. Highly Specialized Ubiquitin-Like Modifications: Shedding Light into the UFM1 Enigma. Witting KF, Mulder MPC. Biomolecules 11 255 (2021)
  9. UFMylation System: An Emerging Player in Tumorigenesis. Jing Y, Mao Z, Chen F. Cancers (Basel) 14 3501 (2022)
  10. The Post-Translational Role of UFMylation in Physiology and Disease. Wang X, Xu X, Wang Z. Cells 12 2543 (2023)

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  1. The replication focus targeting sequence (RFTS) domain is a DNA-competitive inhibitor of Dnmt1. Syeda F, Fagan RL, Wean M, Avvakumov GV, Walker JR, Xue S, Dhe-Paganon S, Brenner C. J Biol Chem 286 15344-15351 (2011)
  2. Insights into noncanonical E1 enzyme activation from the structure of autophagic E1 Atg7 with Atg8. Hong SB, Kim BW, Lee KE, Kim SW, Jeon H, Kim J, Song HK. Nat Struct Mol Biol 18 1323-1330 (2011)
  3. The ufm1 cascade. Daniel J, Liebau E. Cells 3 627-638 (2014)
  4. Mechanistic studies of substrate-assisted inhibition of ubiquitin-activating enzyme by adenosine sulfamate analogues. Chen JJ, Tsu CA, Gavin JM, Milhollen MA, Bruzzese FJ, Mallender WD, Sintchak MD, Bump NJ, Yang X, Ma J, Loke HK, Xu Q, Li P, Bence NF, Brownell JE, Dick LR. J Biol Chem 286 40867-40877 (2011)
  5. UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia. Duan R, Shi Y, Yu L, Zhang G, Li J, Lin Y, Guo J, Wang J, Shen L, Jiang H, Wang G, Tang B. PLoS One 11 e0149039 (2016)
  6. Structural basis for adenylation and thioester bond formation in the ubiquitin E1. Hann ZS, Ji C, Olsen SK, Lu X, Lux MC, Tan DS, Lima CD. Proc Natl Acad Sci U S A 116 15475-15484 (2019)
  7. The ubiquitin-fold modifier 1 (Ufm1) cascade of Caenorhabditis elegans. Hertel P, Daniel J, Stegehake D, Vaupel H, Kailayangiri S, Gruel C, Woltersdorf C, Liebau E. J Biol Chem 288 10661-10671 (2013)
  8. Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme. Lv Z, Yuan L, Atkison JH, Williams KM, Vega R, Sessions EH, Divlianska DB, Davies C, Chen Y, Olsen SK. Nat Commun 9 5145 (2018)
  9. Dissecting the Specificity of Adenosyl Sulfamate Inhibitors Targeting the Ubiquitin-Activating Enzyme. Misra M, Kuhn M, Löbel M, An H, Statsyuk AV, Sotriffer C, Schindelin H. Structure 25 1120-1129.e3 (2017)
  10. An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5. Huber J, Obata M, Gruber J, Akutsu M, Löhr F, Rogova N, Güntert P, Dikic I, Kirkin V, Komatsu M, Dötsch V, Rogov VV. Autophagy 16 256-270 (2020)
  11. Mechanistic study of Uba5 enzyme and the Ufm1 conjugation pathway. Gavin JM, Hoar K, Xu Q, Ma J, Lin Y, Chen J, Chen W, Bruzzese FJ, Harrison S, Mallender WD, Bump NJ, Sintchak MD, Bence NF, Li P, Dick LR, Gould AE, Chen JJ. J Biol Chem 289 22648-22658 (2014)
  12. Comment Tyrosyl DNA phosphodiesterase 2, an enzyme fit for purpose. Caldecott KW. Nat Struct Mol Biol 19 1212-1213 (2012)
  13. Facile synthesis of covalent probes to capture enzymatic intermediates during E1 enzyme catalysis. An H, Statsyuk AV. Chem Commun (Camb) 52 2477-2480 (2016)
  14. A selective inhibitor of the UFM1-activating enzyme, UBA5. da Silva SR, Paiva SL, Bancerz M, Geletu M, Lewis AM, Chen J, Cai Y, Lukkarila JL, Li H, Gunning PT. Bioorg Med Chem Lett 26 4542-4547 (2016)
  15. Bio-Guided Fractionation of Ethanol Extract of Leaves of Esenbeckia alata Kunt (Rutaceae) Led to the Isolation of Two Cytotoxic Quinoline Alkaloids: Evidence of Selectivity Against Leukemia Cells. Álvarez-Caballero JM, Cuca-Suárez LE, Coy-Barrera E. Biomolecules 9 E585 (2019)
  16. Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerization and ATP binding. Mashahreh B, Hassouna F, Soudah N, Cohen-Kfir E, Strulovich R, Haitin Y, Wiener R. FASEB J 32 2794-2802 (2018)
  17. A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1. Wesch N, Löhr F, Rogova N, Dötsch V, Rogov VV. Int J Mol Sci 22 7390 (2021)
  18. Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays. Pan X, Alvarez AN, Ma M, Lu S, Crawford MW, Briere LC, Kanca O, Yamamoto S, Sweetser DA, Wilson JL, Napier RJ, Pruneda JN, Bellen HJ. Elife 12 RP89891 (2023)
  19. Expression, purification, and crystal structure of N-terminal domains of human ubiquitin-activating enzyme (E1). Xie ST. Biosci Biotechnol Biochem 78 1542-1549 (2014)
  20. UFM1-Activating Enzyme 5 (Uba5) Requires an Extension to Get the Job Done Right. Lv Z, Olsen SK. J Mol Biol 431 479-482 (2019)
  21. Closing the gap of ubiquitin activation. Kumar M, Wiener R. Proc Natl Acad Sci U S A 116 15319-15321 (2019)
  22. Label-free affinity screening, design and synthesis of inhibitors targeting the Mycobacterium tuberculosis L-alanine dehydrogenase. Kim HB, Bacik JP, Wu R, Jha RK, Hebron M, Triandafillou C, McCown JE, Baek NI, Kim JH, Kim YJ, Goulding CW, Strauss CEM, Schmidt JG, Shetye GS, Ryoo S, Jo EK, Jeon YH, Hung LW, Terwilliger TC, Kim CY. PLoS One 17 e0277670 (2022)
  23. Loss of DDRGK1 impairs IRE1α UFMylation in spondyloepiphyseal dysplasia. Yang X, Zhou T, Wang X, Xia Y, Cao X, Cheng X, Cao Y, Ma P, Ma H, Qin A, Zhao J. Int J Biol Sci 19 4709-4725 (2023)
  24. Overexpression of UBA5 in Cells Mimics the Phenotype of Cells Lacking UBA5. Kumari S, Banerjee S, Kumar M, Hayashi A, Solaimuthu B, Cohen-Kfir E, Shaul YD, Rouvinski A, Wiener R. Int J Mol Sci 23 7445 (2022)


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