Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1986 Feb;83(4):907–911. doi: 10.1073/pnas.83.4.907

ATP-binding site of adenylate kinase: mechanistic implications of its homology with ras-encoded p21, F1-ATPase, and other nucleotide-binding proteins.

D C Fry, S A Kuby, A S Mildvan
PMCID: PMC322979  PMID: 2869483

Abstract

The MgATP binding site of adenylate kinase, located by a combination of NMR and x-ray diffraction, is near three protein segments, five to seven amino acids in length, that are homologous in sequence to segments found in other nucleotide-binding phosphotransferases, such as myosin and F1-ATPase, ras p21 and transducin GTPases, and cAMP-dependent and src protein kinases, suggesting equivalent mechanistic roles of these segments in all of these proteins. Segment 1 is a glycine-rich flexible loop that, on adenylate kinase, may control access to the ATP-binding site by changing its conformation. Segment 2 is an alpha-helix containing two hydrophobic residues that interact with the adenine-ribose moiety of ATP, and a lysine that may bind to the beta- and gamma-phosphates of ATP. Segment 3 is a hydrophobic strand of parallel beta-pleated sheet, terminated by a carboxylate, that flanks the triphosphate binding site. The various reported mutations of ras p21 that convert it to a transforming agent all appear to involve segment 1, and such substitutions may alter the properties of p21 by hindering a conformational change at this segment. In F1-ATPase, the flexible loop may, by its position, control both the accessibility and the ATP/ADP equilibrium constant on the enzyme.

Full text

PDF
911

Images in this article

909Image
on p.909

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adelstein R. S., Eisenberg E. Regulation and kinetics of the actin-myosin-ATP interaction. Annu Rev Biochem. 1980;49:921–956. doi: 10.1146/annurev.bi.49.070180.004421. [DOI] [PubMed] [Google Scholar]
  2. Amzel L. M., Pedersen P. L. Proton atpases: structure and mechanism. Annu Rev Biochem. 1983;52:801–824. doi: 10.1146/annurev.bi.52.070183.004101. [DOI] [PubMed] [Google Scholar]
  3. Bankier A. T., Deininger P. L., Farrell P. J., Barrell B. G. Sequence analysis of the 17,166 base-pair EcoRI fragment C of B95-8 Epstein-Barr virus. Mol Biol Med. 1983 Jul;1(1):21–45. [PubMed] [Google Scholar]
  4. Banks R. D., Blake C. C., Evans P. R., Haser R., Rice D. W., Hardy G. W., Merrett M., Phillips A. W. Sequence, structure and activity of phosphoglycerate kinase: a possible hinge-bending enzyme. Nature. 1979 Jun 28;279(5716):773–777. doi: 10.1038/279773a0. [DOI] [PubMed] [Google Scholar]
  5. Boyer P. D., Kohlbrenner W. E., McIntosh D. B., Smith L. T., O'Neal C. C. ATP and ADP modulations of catalysis by F1 and Ca2+, Mg2+-ATPases. Ann N Y Acad Sci. 1982;402:65–83. doi: 10.1111/j.1749-6632.1982.tb25732.x. [DOI] [PubMed] [Google Scholar]
  6. Dhar R., Ellis R. W., Shih T. Y., Oroszlan S., Shapiro B., Maizel J., Lowy D., Scolnick E. Nucleotide sequence of the p21 transforming protein of Harvey murine sarcoma virus. Science. 1982 Sep 3;217(4563):934–936. doi: 10.1126/science.6287572. [DOI] [PubMed] [Google Scholar]
  7. Evans P. R., Farrants G. W., Hudson P. J. Phosphofructokinase: structure and control. Philos Trans R Soc Lond B Biol Sci. 1981 Jun 26;293(1063):53–62. doi: 10.1098/rstb.1981.0059. [DOI] [PubMed] [Google Scholar]
  8. Fasano O., Aldrich T., Tamanoi F., Taparowsky E., Furth M., Wigler M. Analysis of the transforming potential of the human H-ras gene by random mutagenesis. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4008–4012. doi: 10.1073/pnas.81.13.4008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fry D. C., Kuby S. A., Mildvan A. S. NMR studies of the MgATP binding site of adenylate kinase and of a 45-residue peptide fragment of the enzyme. Biochemistry. 1985 Aug 13;24(17):4680–4694. doi: 10.1021/bi00338a030. [DOI] [PubMed] [Google Scholar]
  10. Gay N. J., Walker J. E. Homology between human bladder carcinoma oncogene product and mitochondrial ATP-synthase. Nature. 1983 Jan 20;301(5897):262–264. doi: 10.1038/301262a0. [DOI] [PubMed] [Google Scholar]
  11. Gibbs J. B., Ellis R. W., Scolnick E. M. Autophosphorylation of v-Ha-ras p21 is modulated by amino acid residue 12. Proc Natl Acad Sci U S A. 1984 May;81(9):2674–2678. doi: 10.1073/pnas.81.9.2674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gibbs J. B., Sigal I. S., Poe M., Scolnick E. M. Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5704–5708. doi: 10.1073/pnas.81.18.5704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Grubmeyer C., Penefsky H. S. The presence of two hydrolytic sites on beef heart mitochondrial adenosine triphosphatase. J Biol Chem. 1981 Apr 25;256(8):3718–3727. [PubMed] [Google Scholar]
  14. Hamada M., Palmieri R. H., Russell G. A., Kuby S. A. Studies of adenosine triphosphate transphosphorylases. XIV. Equilibrium binding properties of the crystalline rabbit and calf muscle ATP--AMP transphosphorylase (adenylate kinase) and derived peptide fragments. Arch Biochem Biophys. 1979 Jun;195(1):155–177. doi: 10.1016/0003-9861(79)90338-2. [DOI] [PubMed] [Google Scholar]
  15. Hansen E. B., Hansen F. G., von Meyenburg K. The nucleotide sequence of the dnaA gene and the first part of the dnaN gene of Escherichia coli K-12. Nucleic Acids Res. 1982 Nov 25;10(22):7373–7385. doi: 10.1093/nar/10.22.7373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hashimoto E., Takio K., Krebs E. G. Amino acid sequence at the ATP-binding site of cGMP-dependent protein kinase. J Biol Chem. 1982 Jan 25;257(2):727–733. [PubMed] [Google Scholar]
  17. Heil A., Müller G., Noda L., Pinder T., Schirmer H., Schirmer I., von Zabern I. The amino-acid sequence of sarcine adenylate kinase from skeletal muscle. Eur J Biochem. 1974 Mar 15;43(1):131–144. doi: 10.1111/j.1432-1033.1974.tb03393.x. [DOI] [PubMed] [Google Scholar]
  18. Hurley J. B., Simon M. I., Teplow D. B., Robishaw J. D., Gilman A. G. Homologies between signal transducing G proteins and ras gene products. Science. 1984 Nov 16;226(4676):860–862. doi: 10.1126/science.6436980. [DOI] [PubMed] [Google Scholar]
  19. Joubert F. J., Haylett T. Snake venoms. Purification, some properties and amino acid sequence of a phospholipase A2 (DE-I) from Trimeresurus okinavensis (Hime-habu) venom. Hoppe Seylers Z Physiol Chem. 1981 Jul;362(7):997–1006. doi: 10.1515/bchm2.1981.362.2.997. [DOI] [PubMed] [Google Scholar]
  20. Kamps M. P., Taylor S. S., Sefton B. M. Direct evidence that oncogenic tyrosine kinases and cyclic AMP-dependent protein kinase have homologous ATP-binding sites. Nature. 1984 Aug 16;310(5978):589–592. doi: 10.1038/310589a0. [DOI] [PubMed] [Google Scholar]
  21. Kuby S. A., Palmieri R. H., Frischat A., Fischer A. H., Wu L. H., Maland L., Manship M. Studies on adenosine triphosphate transphosphorylases. Amino acid sequence of rabbit muscle ATP-AMP transphosphorylase. Biochemistry. 1984 May 22;23(11):2393–2399. doi: 10.1021/bi00306a012. [DOI] [PubMed] [Google Scholar]
  22. Maloy W. L., Bowien B. U., Zwolinski G. K., Kumar K. G., Wood H. G., Ericsson L. H., Walsh K. A. Amino acid sequence of the biotinyl subunit from transcarboxylase. J Biol Chem. 1979 Nov 25;254(22):11615–11622. [PubMed] [Google Scholar]
  23. McGrath J. P., Capon D. J., Goeddel D. V., Levinson A. D. Comparative biochemical properties of normal and activated human ras p21 protein. Nature. 1984 Aug 23;310(5979):644–649. doi: 10.1038/310644a0. [DOI] [PubMed] [Google Scholar]
  24. McKnight S. L. The nucleotide sequence and transcript map of the herpes simplex virus thymidine kinase gene. Nucleic Acids Res. 1980 Dec 20;8(24):5949–5964. doi: 10.1093/nar/8.24.5949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McLaughlin P. J., Stuart D. I., Klein H. W., Oikonomakos N. G., Johnson L. N. Substrate-cofactor interactions for glycogen phosphorylase b: a binding study in the crystal with heptenitol and heptulose 2-phosphate. Biochemistry. 1984 Nov 20;23(24):5862–5873. doi: 10.1021/bi00319a028. [DOI] [PubMed] [Google Scholar]
  26. Mortenson L. E., Thorneley R. N. Structure and function of nitrogenase. Annu Rev Biochem. 1979;48:387–418. doi: 10.1146/annurev.bi.48.070179.002131. [DOI] [PubMed] [Google Scholar]
  27. Northrop D. B., Wood H. G. Transcarboxylase. VII. Exchange reactions and kinetics of oxalate inhibition. J Biol Chem. 1969 Nov 10;244(21):5820–5827. [PubMed] [Google Scholar]
  28. Pai E. F., Sachsenheimer W., Schirmer R. H., Schulz G. E. Substrate positions and induced-fit in crystalline adenylate kinase. J Mol Biol. 1977 Jul;114(1):37–45. doi: 10.1016/0022-2836(77)90281-9. [DOI] [PubMed] [Google Scholar]
  29. Putney S., Herlihy W., Royal N., Pang H., Aposhian H. V., Pickering L., Belagaje R., Biemann K., Page D., Kuby S. Rabbit muscle creatine phosphokinase. CDNA cloning, primary structure and detection of human homologues. J Biol Chem. 1984 Dec 10;259(23):14317–14320. [PubMed] [Google Scholar]
  30. Reddy E. P., Reynolds R. K., Santos E., Barbacid M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature. 1982 Nov 11;300(5888):149–152. doi: 10.1038/300149a0. [DOI] [PubMed] [Google Scholar]
  31. Richardson J. S. The anatomy and taxonomy of protein structure. Adv Protein Chem. 1981;34:167–339. doi: 10.1016/s0065-3233(08)60520-3. [DOI] [PubMed] [Google Scholar]
  32. Robson R. L. Identification of possible adenine nucleotide-binding sites in nitrogenase Fe- and MoFe-proteins by amino acid sequence comparison. FEBS Lett. 1984 Aug 6;173(2):394–398. doi: 10.1016/0014-5793(84)80812-1. [DOI] [PubMed] [Google Scholar]
  33. Sachsenheimer W., Schulz G. E. Two conformations of crystalline adenylate kinase. J Mol Biol. 1977 Jul;114(1):23–36. doi: 10.1016/0022-2836(77)90280-7. [DOI] [PubMed] [Google Scholar]
  34. Schulz G. E., Elzinga M., Marx F., Schrimer R. H. Three dimensional structure of adenyl kinase. Nature. 1974 Jul 12;250(462):120–123. doi: 10.1038/250120a0. [DOI] [PubMed] [Google Scholar]
  35. Seeburg P. H., Colby W. W., Capon D. J., Goeddel D. V., Levinson A. D. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature. 1984 Nov 1;312(5989):71–75. doi: 10.1038/312071a0. [DOI] [PubMed] [Google Scholar]
  36. Shih T. Y., Stokes P. E., Smythers G. W., Dhar R., Oroszlan S. Characterization of the phosphorylation sites and the surrounding amino acid sequences of the p21 transforming proteins coded for by the Harvey and Kirsten strains of murine sarcoma viruses. J Biol Chem. 1982 Oct 10;257(19):11767–11773. [PubMed] [Google Scholar]
  37. Smith G. M., Mildvan A. S. Nuclear magnetic resonance studies of the nucleotide binding sites of porcine adenylate kinase. Biochemistry. 1982 Nov 23;21(24):6119–6123. doi: 10.1021/bi00267a014. [DOI] [PubMed] [Google Scholar]
  38. Sweet R. W., Yokoyama S., Kamata T., Feramisco J. R., Rosenberg M., Gross M. The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity. Nature. 1984 Sep 20;311(5983):273–275. doi: 10.1038/311273a0. [DOI] [PubMed] [Google Scholar]
  39. Tabin C. J., Bradley S. M., Bargmann C. I., Weinberg R. A., Papageorge A. G., Scolnick E. M., Dhar R., Lowy D. R., Chang E. H. Mechanism of activation of a human oncogene. Nature. 1982 Nov 11;300(5888):143–149. doi: 10.1038/300143a0. [DOI] [PubMed] [Google Scholar]
  40. Titani K., Koide A., Hermann J., Ericsson L. H., Kumar S., Wade R. D., Walsh K. A., Neurath H., Fischer E. H. Complete amino acid sequence of rabbit muscle glycogen phosphorylase. Proc Natl Acad Sci U S A. 1977 Nov;74(11):4762–4766. doi: 10.1073/pnas.74.11.4762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tsuchida N., Ryder T., Ohtsubo E. Nucleotide sequence of the oncogene encoding the p21 transforming protein of Kirsten murine sarcoma virus. Science. 1982 Sep 3;217(4563):937–939. doi: 10.1126/science.6287573. [DOI] [PubMed] [Google Scholar]
  42. Von Zabern I., Wittmann-Liebold B., Untucht-Grau R., Schirmer R. H., Pai E. F. Primary and tertiary structure of the principal human adenylate kinase. Eur J Biochem. 1976 Sep;68(1):281–290. doi: 10.1111/j.1432-1033.1976.tb10787.x. [DOI] [PubMed] [Google Scholar]
  43. Walker J. E., Saraste M., Runswick M. J., Gay N. J. Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1982;1(8):945–951. doi: 10.1002/j.1460-2075.1982.tb01276.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Watson H. C., Walker N. P., Shaw P. J., Bryant T. N., Wendell P. L., Fothergill L. A., Perkins R. E., Conroy S. C., Dobson M. J., Tuite M. F. Sequence and structure of yeast phosphoglycerate kinase. EMBO J. 1982;1(12):1635–1640. doi: 10.1002/j.1460-2075.1982.tb01366.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yuasa Y., Srivastava S. K., Dunn C. Y., Rhim J. S., Reddy E. P., Aaronson S. A. Acquisition of transforming properties by alternative point mutations within c-bas/has human proto-oncogene. Nature. 1983 Jun 30;303(5920):775–779. doi: 10.1038/303775a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES