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. 2012 Jan 16;3(1):60–70. doi: 10.1007/s13238-012-2001-1

Conservation and divergence of Grb7 family of Ras-binding domains

Raju V S Rajala 1,2,3,✉, Ammaji Rajala 1,3, Vivek K Gupta 1,3
PMCID: PMC3402353  NIHMSID: NIHMS391816  PMID: 22271596

Abstract

Ras proteins are signal-transducing GTPases that cycle between inactive GDP-bound and active GTP-bound forms. Ras is a prolific signaling molecule interacting with a spectrum of effector molecules and acting through more than one signaling pathway. The Ras-effector proteins contain a Ras-associating (RA) domain through which these associate with Ras in a GTP-dependent manner. The RA domain is highly conserved among the members of the growth factor receptor-bound (Grb) 7 family of proteins which includes Grb7, Grb10 and Grb14. Our laboratory has reported an unusual observation that RA domain of Grb14 binds to the C-terminal nucleotide binding site of cyclic nucleotide gated channel (CTRCNGA1) and inhibits the channel activity. Molecular modeling of the CTR-CNGA1 displays 50%–70% tertiary structural similarity towards Ras proteins. We named this region as Ras-like domain (RLD). The interaction between RA-Grb14 and RLD-CNGA1 is mediated through a simple protein-protein interaction temporally and spatially regulated by light and cGMP. It is interesting to note that Grb14 binds to GTPase-mutant Rab5, a Ras-related small GTPase whereas Grb10 binds only to GTP-bound form of active Rab5 but not to GTPase-defective mutant Rab5. These results suggest that Grb14 might have been evolved later in the evolution that binds to both Ras and nucleotide binding proteins such as CNGA1. Our studies also suggest that eukaryotic CNG channels could be evolved through a gene fusion between prokaryotic ion channels and cyclic nucleotide binding proteins, both of which might have undergone several sequence variations for functional adaptation during evolution.

Keywords: growth factor receptor-bound protein 14, Ras-associating domain, cyclic nucleotide gated channel, rod outer segments, tyrosine kinase signaling, Ras proteins

References

  1. Bourne H.R., Sanders D.A., McCormick F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature. 1990;348:125–132. doi: 10.1038/348125a0. [DOI] [PubMed] [Google Scholar]
  2. Eswar N., Eramian D., Webb B., Shen M.Y., Sali A. Protein structure modeling with MODELLER. Methods Mol Biol. 2008;426:145–159. doi: 10.1007/978-1-60327-058-8_8. [DOI] [PubMed] [Google Scholar]
  3. Guex N., Peitsch M.C. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis. 1997;18:2714–2723. doi: 10.1002/elps.1150181505. [DOI] [PubMed] [Google Scholar]
  4. Gupta V., Rajala A., Rodgers K., Rajala R.V. Mechanism Involved in the Modulation of Photoreceptor-Specific Cyclic Nucleotide-Gated Channel by the Tyrosine Kinase Adapter Protein Grb14. Protein Cell. 2011;2:906–917. doi: 10.1007/s13238-011-1115-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gupta V.K., Rajala A., Daly R.J., Rajala R.V. Growth factor receptor-bound protein 14: a new modulator of photoreceptor-specific cyclic-nucleotide-gated channel. EMBO Rep. 2010;11:861–867. doi: 10.1038/embor.2010.142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hargrave P.A. Rhodopsin structure, function, and topography the Friedenwald lecture. Invest Ophthalmol Vis Sci. 2001;42:3–9. [PubMed] [Google Scholar]
  7. Hargrave P.A., McDowell J.H. Rhodopsin and phototransduction. Int Rev Cytol. 1992;137B:49–97. doi: 10.1016/s0074-7696(08)62600-5. [DOI] [PubMed] [Google Scholar]
  8. Hargrave P.A., McDowell J.H. Rhodopsin and phototransduction: a model system for G protein-linked receptors. FASEB J. 1992;6:2323–2331. doi: 10.1096/fasebj.6.6.1544542. [DOI] [PubMed] [Google Scholar]
  9. Holm L., Kääriäinen S., Rosenström P., Schenkel A. Searching protein structure databases with DaliLite v. Bioinformatics. 2008;24:2780–2781. doi: 10.1093/bioinformatics/btn507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Humphrey W., Dalke A., Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14:33–38. doi: 10.1016/0263-7855(96)00018-5. [DOI] [PubMed] [Google Scholar]
  11. Kanan Y., Matsumoto H., Song H., Sokolov M., Anderson R.E., Rajala R.V. Serine/threonine kinase akt activation regulates the activity of retinal serine/threonine phosphatases, PHLPP and PHLPPL. J Neurochem. 2010;113:477–488. doi: 10.1111/j.1471-4159.2010.06609.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kannan N., Wu J., Anand G.S., Yooseph S., Neuwald A.F., Venter J.C., Taylor S.S. Evolution of allostery in the cyclic nucleotide binding module. Genome Biol. 2007;8:R264. doi: 10.1186/gb-2007-8-12-r264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Karnoub A.E., Weinberg R.A. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9:517–531. doi: 10.1038/nrm2438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kaupp U.B., Seifert R. Cyclic nucleotide-gated ion channels. Physiol Rev. 2002;82:769–824. doi: 10.1152/physrev.00008.2002. [DOI] [PubMed] [Google Scholar]
  15. Kyriakis J.M. Thinking outside the box about Ras. J Biol Chem. 2009;284:10993–10994. doi: 10.1074/jbc.R800085200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Li G., Anderson R.E., Tomita H., Adler R., Liu X., Zack D.J., Rajala R.V. Nonredundant role of Akt2 for neuroprotection of rod photoreceptor cells from light-induced cell death. J Neurosci. 2007;27:203–211. doi: 10.1523/JNEUROSCI.0445-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Liang Z., Mather T., Li G. GTPase mechanism and function: new insights from systematic mutational analysis of the phosphate-binding loop residue Ala30 of Rab5. Biochem J. 2000;346:501–508. doi: 10.1042/bj3460501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Magee T., Marshall C. New insights into the interaction of Ras with the plasma membrane. Cell. 1999;98:9–12. doi: 10.1016/S0092-8674(00)80601-7. [DOI] [PubMed] [Google Scholar]
  19. McCormick F., Wittinghofer A. Interactions between Ras proteins and their effectors. Curr Opin Biotechnol. 1996;7:449–456. doi: 10.1016/S0958-1669(96)80123-6. [DOI] [PubMed] [Google Scholar]
  20. McKay D.B., Steitz T.A. Structure of catabolite gene activator protein at 2.9 A resolution suggests binding to left-handed B-DNA. Nature. 1981;290:744–749. doi: 10.1038/290744a0. [DOI] [PubMed] [Google Scholar]
  21. Morris A.L., MacArthur M.W., Hutchinson E.G., Thornton J.M. Stereochemical quality of protein structure coordinates. Proteins. 1992;12:345–364. doi: 10.1002/prot.340120407. [DOI] [PubMed] [Google Scholar]
  22. Papermaster D.S. Preparation of retinal rod outer segments. Methods Enzymol. 1982;81:48–52. doi: 10.1016/S0076-6879(82)81010-0. [DOI] [PubMed] [Google Scholar]
  23. Ponting C.P., Benjamin D.R. A novel family of Ras-binding domains. Trends Biochem Sci. 1996;21:422–425. doi: 10.1016/S0968-0004(96)30038-8. [DOI] [PubMed] [Google Scholar]
  24. Raaijmakers J.H., Bos J.L. Specificity in Ras and Rap signaling. J Biol Chem. 2009;284:10995–10999. doi: 10.1074/jbc.R800061200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rajala A., Daly R.J., Tanito M., Allen D.T., Holt L.J., Lobanova E. S., Arshavsky V.Y., Rajala R.V. Growth factor receptor-bound protein 14 undergoes light-dependent intracellular translocation in rod photoreceptors: functional role in retinal insulin receptor activation. Biochemistry. 2009;48:5563–5572. doi: 10.1021/bi9000062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rajala R.V., McClellan M.E., Ash J.D., Anderson R.E. In vivo regulation of phosphoinositide 3-kinase in retina through light-induced tyrosine phosphorylation of the insulin receptor beta-subunit. J Biol Chem. 2002;277:43319–43326. doi: 10.1074/jbc.M206355200. [DOI] [PubMed] [Google Scholar]
  27. Smith H.G., Jr, Litman B.J. Preparation of osmotically intact rod outer segment disks by Ficoll flotation. Methods Enzymol. 1982;81:57–61. doi: 10.1016/S0076-6879(82)81012-4. [DOI] [PubMed] [Google Scholar]
  28. Symons M., Takai Y. Ras GTPases: singing in tune. Sci STKE. 2001;2001:E1. doi: 10.1126/stke.2001.68.pe1. [DOI] [PubMed] [Google Scholar]
  29. van der Weyden L., Adams D.J. The Ras-association domain family (RASSF) members and their role in human tumourigenesis. Biochim Biophys Acta. 2007;1776:58–85. doi: 10.1016/j.bbcan.2007.06.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vriend G. WHAT IF: a molecular modeling and drug design program. J Mol Graph. 1990;8:52–56. doi: 10.1016/0263-7855(90)80070-V. [DOI] [PubMed] [Google Scholar]
  31. Weber I.T., Takio K., Titani K., Steitz T.A. The cAMPbinding domains of the regulatory subunit of cAMP-dependent protein kinase and the catabolite gene activator protein are homologous. Proc Natl Acad Sci U S A. 1982;79:7679–7683. doi: 10.1073/pnas.79.24.7679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wigler M., Pellicer A., Silverstein S., Axel R. Biochemical transfer of single-copy eucaryotic genes using total cellular DNA as donor. Cell. 1978;14:725–731. doi: 10.1016/0092-8674(78)90254-4. [DOI] [PubMed] [Google Scholar]

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