ABC  Vol.3 No.4 , August 2013
In silico analysis of influence of the missense mutation P629S on the molecular interaction and 3D properties of PIK3R5
PIK3R5 is the regulatory subunit of Phosphoinositide 3-kinase γ (PI3Kγ) that is responsible for phosphory-lating membrane lipids to activate the AKT pathway. PIK3R5 binds Gβγ and facilitates the interaction with p110γ catalytic subunit (PIK3CG) during PI3Kγ activation. The identification of PIK3R5 P629S mutation in AOA2 patients indicated a potential defect in the AKT pathway resulting from impaired PIK3R5 interaction with Gβγ and PIK3CG, defective AKT pathway can result in cerebellar cell death causing neurological symptoms. Our in silico macromolecular docking of the wild type and mutant PIK3R5 protein models with ligand revealed an energy requirement to maintain the mutant complexes compared to no energy required to maintain the wild type complexes, in addition, the mutant structures were loose compared to rigid wild type structures, such structural changes may impair the molecular function of the PIK3R5 and hence affect the AKT pathway.

Cite this paper
Shinwari, J. , Tahir, A. , Bohlega, S. and AlTassan, N. (2013) In silico analysis of influence of the missense mutation P629S on the molecular interaction and 3D properties of PIK3R5. Advances in Biological Chemistry, 3, 408-417. doi: 10.4236/abc.2013.34044.
[1]   [1] Chen, K., Iribarren, P., Gong, W. and Wang, J.M. (2005) The essential role of phosphoinositide 3-kinases (PI3Ks) in regulating pro-inflammatory responses and the progression of cancer. Cellular & Molecular Immunology, 2, 241-252.

[2]   Shymanets, A., Ahmadian, M.R., Kossmeier, K.T., Wetzker, R., Harteneck, C. and Nurnberg, B. (2012) The p101 subunit of PI3Kgamma restores activation by Gbeta mutants deficient in stimulating p110gamma. The Journal of Biological Chemistry, 441, 851-858. doi:10.1042/BJ20111664

[3]   Brock, C., Schaefer, M., Reusch, H.P., Czupalla, C., Michalke, M., Spicher, K., Schultz, G. and Nurnberg, B. (2003) Roles of G beta gamma in membrane recruitment and activation of p110 gamma/p101 phosphoinositide 3-kinase gamma. The Journal of Cell Biology, 160, 89-99. doi:10.1083/jcb.200210115

[4]   Osaki, M., Oshimura, M. and Ito, H. (2004) PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis, 9, 667-676. doi:10.1023/B:APPT.0000045801.15585.dd

[5]   Zhao, L. and Vogt, P.K. (2008) Class I PI3K in oncogenic cellular transformation. Oncogene, 27, 5486-5496. doi:10.1038/onc.2008.244

[6]   Vanhaesebroeck, B. and Alessi, D.R. (2000) The PI3K-PDK1 connection: More than just a road to PKB. The Journal of Biological Chemistry, 346, 561-576. doi:10.1042/0264-6021:3460561

[7]   Walker, E.H., Perisic, O., Ried, C., Stephens, L. and Williams, R.L. (1999) Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature, 402, 313-320. doi:10.1038/46319

[8]   Voigt, P., Brock, C., Nurnberg, B. and Schaefer, M. (2005) Assigning functional domains within the p101 regulatory subunit of phosphoinositide 3-kinase gamma. The Journal of Biological Chemistry, 280, 5121-5127. doi:10.1074/jbc.M413104200

[9]   Skorski, T., Bellacosa, A., Nieborowska-Skorska, M., Majewski, M., Martinez, R., Choi, J.K., Trotta, R., Wlodarski, P., Perrotti, D., Chan, T.O., et al (1997) Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO Journal, 16, 6151-6161. doi:10.1093/emboj/16.20.6151

[10]   Benistant, C., Chapuis, H. and Roche, S. (2000) A specific function for phosphatidylinositol 3-kinase alpha (p85al-pha-p110alpha) in cell survival and for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in de novo DNA synthesis of human colon carcinoma cells. Oncogene, 19, 5083-5090. doi:10.1038/sj.onc.1203871

[11]   Knobbe, C.B., Trampe-Kieslich, A. and Reifenberger, G. (2005) Genetic alteration and expression of the phosphorinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. Neuropathology and Applied Neurobiology, 31, 486-490. doi:10.1111/j.1365-2990.2005.00660.x

[12]   Mizoguchi, M., Nutt, C.L., Mohapatra, G. and Louis, D.N. (2004) Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. Brain Pathology, 14, 372-377. doi:10.1111/j.1750-3639.2004.tb00080.x

[13]   Al Tassan, N., Khalil, D., Shinwari, J., Al Sharif, L., Bavi, P., Abduljaleel, Z., Abu Dhaim, N., Magrashi, A., Bobis, S., Ahmed, H., et al. (2012) A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia. Human Mutation, 33, 351-354. doi:10.1002/humu.21650

[14]   Moreira, M.C., Klur, S., Watanabe, M., Nemeth, A.H., Le Ber, I., Moniz, J.C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., et al. (2004) Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nature Genetics, 36, 225-227. doi:10.1038/ng1303

[15]   Amouri, R., Moreira, M.C., Zouari, M., El Euch, G., Barhoumi, C., Kefi, M., Belal, S., Koenig, M. and Hentati, F. (2004) Aprataxin gene mutations in Tunisian families. Neurology, 63, 928-929. doi:10.1212/01.WNL.0000137044.06573.46

[16]   Fernet, M., Gribaa, M., Salih, M.A., Seidahmed, M.Z., Hall, J. and Koenig, M. (2005) Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder. Human Molecular Genetics, 14, 307-318. doi:10.1093/hmg/ddi027

[17]   Zhang, Z., Miteva, M.A., Wang, L. and Alexov, E. (2012) Analyzing effects of naturally occurring missense mutations. Computational and Mathematical Methods in Medicine, 2012, 805827. doi:10.1155/2012/805827

[18]   Roy, A., Kucukural, A. and Zhang, Y. (2010) I-TASSER: A unified platform for automated protein structure and function prediction. Nature Protocols, 5, 725-738. doi:10.1038/nprot.2010.5

[19]   Zhang, Y. (2007) Template-based modeling and free modeling by I-TASSER in CASP7. Proteins: Structure, Function, and Bioinformatics, 69, 108-117. doi:10.1002/prot.21702

[20]   Wu, S. and Zhang, Y. (2007) LOMETS: A local metathreading-server for protein structure prediction. Nucleic Acids Research, 35, 3375-3382. doi:10.1093/nar/gkm251

[21]   Sali, A. and Blundell, T.L. (1994) Comparative protein modelling by satisfaction of spatial restraints. Protein Structure by Distance Analysis, 64, C86. doi:10.1006/jmbi.1993.1626

[22]   Tuncbag, N., Gursoy, A. and Keskin, O. (2009) Identification of computational hot spots in protein interfaces: Combining solvent accessibility and inter-residue potentials improves the accuracy. Bioinformatics, 25, 1513-1520. doi:10.1093/bioinformatics/btp240

[23]   Pontius, J., Richelle, J. and Wodak, S.J. (1996) Deviations from standard atomic volumes as a quality measure for protein crystal structures. Journal of Molecular Biology, 264, 121-136. doi:10.1006/jmbi.1996.0628

[24]   Luthy, R., Bowie, J.U. and Eisenberg, D. (1992) Assessment of protein models with three-dimensional profiles. Nature, 356, 83-85. doi:10.1038/356083a0

[25]   Laskowski, R.A., MacArthur, M.W., Moss, D.S. and Thornton, J.M. (1993) PROCHECK: A program to check the stereochemical quality of protein structures. Journal of Applied Crystallography, 26, 283-291. doi:10.1107/S0021889892009944

[26]   Lovell, S.C., Davis, I.W., Arendall, W.B., de Bakker, P.I., Word, J.M., Prisant, M.G., Richardson, J.S. and Richardson, D.C. (2003) Structure validation by Calpha geometry: Phi,psi and Cbeta deviation. Proteins, 50, 437-450. doi:10.1002/prot.10286

[27]   Guex, N. and Peitsch, M.C. (1997) SWISS-MODEL and the Swiss-Pdb Viewer: An environment for comparative protein modeling. Electrophoresis, 18, 2714-2723. doi:10.1002/elps.1150181505

[28]   Roger, S. and Milner-White, E.J. (1995) RasMol: Biomolecular graphics for all. Trends in Biochemical Sciences (TIBS), 20, 374. doi:10.1016/S0968-0004(00)89080-5

[29]   Ritchie, D.W. and Venkatraman, V. (2010) Ultra-fast FFT protein docking on graphics processors. Bioinformatics, 26, 2398-2405. doi:10.1093/bioinformatics/btq444

[30]   Dombkowski, A.A. (2003) Disulfide by DesignTM: A computational method for the rational design of disulfide bonds in proteins. Bioinformatics, 19, 1852-1853. doi:10.1093/bioinformatics/btg231

[31]   Herbert, J.B. (2000) Recent changes to RasMol, recombining the variants. Trends in Biochemical Sciences, 25, pp. 453-455. doi:10.1016/S0968-0004(00)01606-6

[32]   Chen, V.B., Arendall 3rd, W.B., Headd, J.J., Keedy, D.A., Immormino, R.M., Kapral, G.J., Murray, L.W., Richardson, J.S. and Richardson, D.C. (2010) MolProbity: Allatom structure validation for macromolecular crystallography. Acta Crystallographica Section D: Biological Crystallography, 66, 12-21. doi:10.1107/S0907444909042073

[33]   Chen, V.B., Davis, I.W. and Richardson, D.C. (2009) KING (Kinemage, Next Generation): A versatile interactive molecular and scientific visualization program. Protein Science, 18, 2403-2409. doi:10.1002/pro.250

[34]   Colovos, C. and Yeates, T.O. (1993) Verification of protein structures: Patterns of nonbonded atomic interactions. Protein Science, 2, 1511-1519. doi:10.1002/pro.5560020916

[35]   Olson, A.J. and Goodsell, D.S. (2007) A semiempirical free energy force field with charge-based desolvation. Journal of Computational Chemistry, 28, 1145-1152. doi:10.1002/jcc.20634

[36]   Koukouritaki, S.B., Poch, M.T., Henderson, M.C., Siddens, L.K., Krueger, S.K., VanDyke, J.E., Williams, D.E., Pajewski, N.M., Wang, T. and Hines, R.N. (2007) Identification and functional analysis of common human flavincontaining monooxygenase 3 genetic variants. Journal of Pharmacology and Experimental Therapeutics, 320, 266-273. doi:10.1124/jpet.106.112268

[37]   Tang, K.E. and Dill, K.A. (1998) Native protein fluctuations: The conformational-motion temperature and the inverse correlation of protein flexibility with protein stability. Journal of Biomolecular Structure & Dynamics, 16, 397-411. doi:10.1080/07391102.1998.10508256

[38]   Board, P.G., Pierce, K. and Coggan, M. (1990) Expression of functional coagulation factor XIII in Escherichia coli. Journal of Thrombosis and Haemostasis, 63, 235-240.

[39]   Deber, C.M., Brodsky, B. and Rath, A. (2010) Proline residues in proteins. John Wiley & Sons Ltd., Chichester.

[40]   Williamson, M.P. (1994) The structure and function of proline-rich regions in proteins. Biochemical Journal, 297, 249-260.

[41]   Kini, R.M. and Evans, H.J. (1995) A hypothetical structural role for proline residues in the flanking segments of protein-protein interaction sites. Biochemical and Biophysical Research Communications, 212, 1115-1124. doi:10.1006/bbrc.1995.2084

[42]   Kay, B.K., Williamson, M.P. and Sudol, M. (2000) The importance of being proline: The interaction of prolinerich motifs in signaling proteins with their cognate domains. The FASEB Journal, 14, 231-241.