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Identification of unknown protein function using metabolite cocktail screening.

Shumilin IA, Cymborowski M, Chertihin O, Jha KN, Herr JC, Lesley SA, Joachimiak A, Minor W
Structure 20 1715-25 (2012)

Cited: 34 times
EuropePMC logo PMID: 22940582

Abstract

Proteins of unknown function comprise a significant fraction of sequenced genomes. Defining the roles of these proteins is vital to understanding cellular processes. Here, we describe a method to determine a protein function based on the identification of its natural ligand(s) by the crystallographic screening of the binding of a metabolite library, followed by a focused search in the metabolic space. The method was applied to two protein families with unknown function, PF01256 and YjeF_N. The PF01256 proteins, represented by YxkO from Bacillus subtilis and the C-terminal domain of Tm0922 from Thermotoga maritima, were shown to catalyze ADP/ATP-dependent NAD(P)H-hydrate dehydratation, a previously described orphan activity. The YjeF_N proteins, represented by mouse apolipoprotein A-I binding protein and the N-terminal domain of Tm0922, were found to interact with an adenosine diphosphoribose-related substrate and likely serve as ADP-ribosyltransferases. Crystallographic screening of metabolites serves as an efficient tool in functional analyses of uncharacterized proteins.

Reviews citing this publication (11)

  1. Zebrafish models of dyslipidemia: relevance to atherosclerosis and angiogenesis. Fang L, Liu C, Miller YI. Transl Res 163 99-108 (2014)
  2. Metabolite proofreading, a neglected aspect of intermediary metabolism. Van Schaftingen E, Rzem R, Marbaix A, Collard F, Veiga-da-Cunha M, Linster CL. J Inherit Metab Dis 36 427-434 (2013)
  3. Protein crystallography for aspiring crystallographers or how to avoid pitfalls and traps in macromolecular structure determination. Wlodawer A, Minor W, Dauter Z, Jaskolski M. FEBS J 280 5705-5736 (2013)
  4. Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery. Patel D, Bauman JD, Arnold E. Prog Biophys Mol Biol 116 92-100 (2014)
  5. Cryo-EM: beyond the microscope. Earl LA, Falconieri V, Milne JL, Subramaniam S. Curr Opin Struct Biol 46 71-78 (2017)
  6. The impact of structural genomics: the first quindecennial. Grabowski M, Niedzialkowska E, Zimmerman MD, Minor W. J Struct Funct Genomics 17 1-16 (2016)
  7. The future of crystallography in drug discovery. Zheng H, Hou J, Zimmerman MD, Wlodawer A, Minor W. Expert Opin Drug Discov 9 125-137 (2014)
  8. X-ray crystallography over the past decade for novel drug discovery - where are we heading next? Zheng H, Handing KB, Zimmerman MD, Shabalin IG, Almo SC, Minor W. Expert Opin Drug Discov 10 975-989 (2015)
  9. AIBP, Angiogenesis, Hematopoiesis, and Atherogenesis. Qiu X, Luo J, Fang L. Curr Atheroscler Rep 23 1 (2020)
  10. Single-Stranded DNA Binding Proteins and Their Identification Using Machine Learning-Based Approaches. Guo JT, Malik F. Biomolecules 12 1187 (2022)
  11. The mysterious diadenosine tetraphosphate (AP4A). Zegarra V, Mais CN, Freitag J, Bange G. Microlife 4 uqad016 (2023)

Articles citing this publication (23)

  1. Apolipoprotein A-1 binding protein promotes macrophage cholesterol efflux by facilitating apolipoprotein A-1 binding to ABCA1 and preventing ABCA1 degradation. Zhang M, Li L, Xie W, Wu JF, Yao F, Tan YL, Xia XD, Liu XY, Liu D, Lan G, Zeng MY, Gong D, Cheng HP, Huang C, Zhao ZW, Zheng XL, Tang CK. Atherosclerosis 248 149-159 (2016)
  2. Occurrence and subcellular distribution of the NADPHX repair system in mammals. Marbaix AY, Tyteca D, Niehaus TD, Hanson AD, Linster CL, Van Schaftingen E. Biochem J 460 49-58 (2014)
  3. Confronting the catalytic dark matter encoded by sequenced genomes. Ellens KW, Christian N, Singh C, Satagopam VP, May P, Linster CL. Nucleic Acids Res 45 11495-11514 (2017)
  4. AIBP protects against metabolic abnormalities and atherosclerosis. Schneider DA, Choi SH, Agatisa-Boyle C, Zhu L, Kim J, Pattison J, Sears DD, Gordts PLSM, Fang L, Miller YI. J Lipid Res 59 854-863 (2018)
  5. Structural, functional, and inhibition studies of a Gcn5-related N-acetyltransferase (GNAT) superfamily protein PA4794: a new C-terminal lysine protein acetyltransferase from pseudomonas aeruginosa. Majorek KA, Kuhn ML, Chruszcz M, Anderson WF, Minor W. J Biol Chem 288 30223-30235 (2013)
  6. Refining the macromolecular model - achieving the best agreement with the data from X-ray diffraction experiment. Shabalin IG, Porebski PJ, Minor W. Crystallogr Rev 24 236-262 (2018)
  7. AIBP augments cholesterol efflux from alveolar macrophages to surfactant and reduces acute lung inflammation. Choi SH, Wallace AM, Schneider DA, Burg E, Kim J, Alekseeva E, Ubags ND, Cool CD, Fang L, Suratt BT, Miller YI. JCI Insight 3 120519 (2018)
  8. A pathway for repair of NAD(P)H in plants. Colinas M, Shaw HV, Loubéry S, Kaufmann M, Moulin M, Fitzpatrick TB. J Biol Chem 289 14692-14706 (2014)
  9. AIBP protects retinal ganglion cells against neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration. Choi SH, Kim KY, Perkins GA, Phan S, Edwards G, Xia Y, Kim J, Skowronska-Krawczyk D, Weinreb RN, Ellisman MH, Miller YI, Ju WK. Redox Biol 37 101703 (2020)
  10. Evidence that the metabolite repair enzyme NAD(P)HX epimerase has a moonlighting function. Niehaus TD, Elbadawi-Sidhu M, Huang L, Prunetti L, Gregory JF, de Crécy-Lagard V, Fiehn O, Hanson AD. Biosci Rep 38 BSR20180223 (2018)
  11. Intracellular AIBP (Apolipoprotein A-I Binding Protein) Regulates Oxidized LDL (Low-Density Lipoprotein)-Induced Mitophagy in Macrophages. Choi SH, Agatisa-Boyle C, Gonen A, Kim A, Kim J, Alekseeva E, Tsimikas S, Miller YI. Arterioscler Thromb Vasc Biol 41 e82-e96 (2021)
  12. Cholesterol Efflux-Independent Modification of Lipid Rafts by AIBP (Apolipoprotein A-I Binding Protein). Low H, Mukhamedova N, Capettini LDSA, Xia Y, Carmichael I, Cody SH, Huynh K, Ditiatkovski M, Ohkawa R, Bukrinsky M, Meikle PJ, Choi SH, Field S, Miller YI, Sviridov D. Arterioscler Thromb Vasc Biol 40 2346-2359 (2020)
  13. Edc3 function in yeast and mammals is modulated by interaction with NAD-related compounds. Walters RW, Shumilin IA, Yoon JH, Minor W, Parker R. G3 (Bethesda) 4 613-622 (2014)
  14. Mitochondrial apolipoprotein A-I binding protein alleviates atherosclerosis by regulating mitophagy and macrophage polarization. Duan M, Chen H, Yin L, Zhu X, Novák P, Lv Y, Zhao G, Yin K. Cell Commun Signal 20 60 (2022)
  15. NAD(P)H-hydrate dehydratase- a metabolic repair enzyme and its role in Bacillus subtilis stress adaptation. Petrovova M, Tkadlec J, Dvoracek L, Streitova E, Licha I. PLoS One 9 e112590 (2014)
  16. NPF:network propagation for protein function prediction. Zhao B, Zhang Z, Jiang M, Hu S, Luo Y, Wang L. BMC Bioinformatics 21 355 (2020)
  17. Systemic metabolite profiling reveals sexual dimorphism of AIBP control of metabolism in mice. Kim JD, Zhu L, Sun Q, Fang L. PLoS One 16 e0248964 (2021)
  18. Structure and properties of AB21, a novel Agaricus bisporus protein with structural relation to bacterial pore-forming toxins. Komárek J, Ivanov Kavková E, Houser J, Horáčková A, Ždánská J, Demo G, Wimmerová M. Proteins 86 897-911 (2018)
  19. Fragment and conquer: from structure to complexes to function. Guichou JF, Labesse G. Structure 20 1617-1619 (2012)
  20. AIBP Regulates Metabolism of Ketone and Lipids but Not Mitochondrial Respiration. Kim JD, Zhou T, Zhang A, Li S, Gupte AA, Hamilton DJ, Fang L. Cells 11 3643 (2022)
  21. Identification of the ligand in the structure of the protein with unknown function STM4435 from Salmonella typhimurium. Boyko KM, Gorbacheva MA, Rakitina TV, Korzhenevsky DA, Dorovatovsky PV, Lipkin AV, Popov VO. Dokl Biochem Biophys 457 121-124 (2014)
  22. PYRIDOX(AM)INE 5'-PHOSPHATE OXIDASE3 of Arabidopsis thaliana maintains carbon/nitrogen balance in distinct environmental conditions. Steensma P, Eisenhut M, Colinas M, Rosado-Souza L, Fernie AR, Weber APM, Fitzpatrick TB. Plant Physiol 193 1433-1455 (2023)
  23. To Explore the Binding Affinity of Human γ-Secretase Activating Protein (GSAP) Isoform 4 with APP-C99 Peptides. Angira D, Chaudhary S, Abiramasundari A, Thiruvenkatam V. ACS Omega 8 13435-13443 (2023)


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