Abstract
GTPase activating protein (GAP) is a known regulator of ras-p21 activity and is a likely target of ras-induced mitogenic signaling. The domains of GAP that may be involved in this signaling are unknown. In order to infer which domains of GAP may be involved, we have performed molecular dynamics calculations of GAP complexed to wild-type and oncogenic (Val 12–containing) ras-p21, both bound to GTP. We have computed and superimposed the average structures for both complexes and find that there are four domains of GAP that undergo major changes in conformation: residues 821–851, 917–924, 943–953, and 1003–1020. With the exception of the 943–953 domain, none of these domains is involved in making contacts with ras-p21, and all of them occur on the surface of the protein, making them good candidates for effector domains. In addition, three ras-p21 domains undergo major structural changes in the oncogenic p21-GAP complex: 71–76 from the switch 2 domain; 100–108, which interacts with SOS, jun and jun kinase (JNK); and residues 122–138. The change in conformation of the 71–76 domain appears to be induced by changes in conformation in the switch 1 domain (residues 32–40) and in the adjacent domain involving residues 21–31. In an accompanying paper, we present results from microinjection of peptides corresponding to each of these domains into oocytes induced to undergo maturation by oncogenic ras-p21 and by insulin-activated wild-type cellular p21 to determine whether these domain peptides may be involved in ras signaling through GAP.
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REFERENCES
Adler, V., Pincus, M. R., Brandt-Rauf, P. W., and Ronai, Z. (1995). Proc. Natl. Acad. Sci. USA 92, 10585–10589.
Adler, V., Pincus, M. R., Polatskaya, A., Montano, X., Friedman, F. K., and Ronai, Z. (1996). J. Biol. Chem. 271, 23304–23309.
Amar, S., Glozman, A., Chung, D. L., Alder, V., Ronai, Z., Friedman, F. K., Robinson, R., Brandt-Rauf, P. W., Yamaizumi, Z., and Pincus, M. R. (1997). Cancer Chemother. Pharmacol. 41, 79–85.
Barbacid, M. (1987). Annu. Rev. Biochem. 56, 779–827.
Birchmeier, C., Broek, D., and Wigler, M. (1985). Cell 43, 615–621.
Boriak-Sjodin, P. A., Margarit, S. M., Bar-Sagi, D., and Kuriyan, J. (1998). Nature (London) 394, 337–343.
Chen, J., Lee, G., Murphy, R. B., Carty, R. P., Brandt-Rauf, P. W., Friedman, E., and Pincus, M. R. (1989). J. Biomol. Struct. Dynamics 6, 859–875.
Chen, J. M., Monaco, R., Manolatos, S., Brandt-Rauf, P. W., Friedman, F. K., and Pincus, M. R. (1997). J. Prot. Chem. 16, 631–635.
Chen, J. M., Friedman, F. K., Hyde, M. J., Monaco, R., and Pincus, M. R. (1999). J. Prot. Chem. 18, 867–874.
Chie, L., Chen, J. M., Friedman, F. K., Chung, D. L., Amar, S., Michl, J., Yamaizumi, Z., and Pincus, M. R. (1999a). J. Prot. Chem. 18, 875–879.
Chie, L., Chen J. M., Friedman, F. K., Chung, D. L., Amar, S., Michl, J., Yamaizumi, Z., Brandt-Rauf, P. W., and Pincus, M. R. (1999b). J. Prot. Chem. 18, 881–884.
Chie, L., Friedman, F. K., Kung, H.-F., Lin, M., Chung, D., and Pincus, M. R. (2002). J. Prot. Chem. 21, 367–370.
Chung, D. L., Joran, A., Friedman, F. K., Robinson, R. R., Brandt-Rauf, P. W., Weinstein, I. B., Ronai, Z. A., Baskin, L., Dykes, D. C., Murphy, R. B., Nishimura, S. Yamaizumi, Z., and Pincus, M. R. (1992a). Exp. Cell Res. 203, 329–335.
Chung, D. L., Brandt-Rauf, P. W., Weinstein, I. B., Nishimura, S., Yamaizumi, Z., Murphy, R. B., and Pincus, M. R. (1992b). Proc. Natl. Acad. Sci. USA 89, 1993–1996.
Chung, D., Amar, S., Glozman, A., Chen, J. M., Friedman, F. K., Robinson, R., Monaco, R., Brandt-Rauf, P. W., Yamaizumi, Z., and Pincus, M. R. (1997). J. Prot. Chem. 16, 619–629.
Clanton, D. J., Lu, Y., Blair, D. G., and Shih, T. Y. (1987). Mol. Cell. Biol. 7, 3092–3097.
Clark, G. J., Westwick, J. K., and Der, C. J. (1997). J. Biol. Chem. 272, 1677–1681.
Der, C. J., Finkel, T., and Cooper, G. M. (1986). Cell 44, 167–176.
Deshpande, A. K. and Kung, H.-F. (1987). Mol. Cell. Biol. 7, 1285–1288.
Dykes, D. C., Friedman, F. K., Luster, S. M., Murphy, R. B., Brandt-Rauf, P. W., and Pincus, M. R. (1993). J. Biomol. Struct. Dynamics 11, 443–458.
Friedman, F. K., Chie, L., Chung, D. L., Robinson, R., Brandt-Rauf, P. W., Yamaizumi, Z., and Pincus, M. R. (2002). J. Prot. Chem. 21, 361–366.
Krengel, U., Schlichting, L., Scherer, A., Schumann, R., Frech, M., John, J., Kabsch, W., Pai, E. F., and Wittinghofer, A. (1990). Cell 62, 539–548.
Liwo, A., Gibson, K. D., Scheraga, H. A., Brandt-Rauf, P. W., Monaco, R., and Pincus, M. R. (1994). J. Prot. Chem. 13, 237–251.
Monaco, R., Chen, J. M., Chung, D. L., Brandt-Rauf, P. W., and Pincus, M. R. (1995a). J. Prot. Chem. 14, 457–466.
Monaco, R., Chen, J. M., Friedman, F. K., Brandt-Rauf, P. W., and Pincus, M. R. (1995b). J. Prot. Chem. 14, 721–730.
Moodie, S. A., Willumsen, B. M., Weber, M. J., and Wolfman, A. (1993). Science 260, 1658–1661.
Nassar, N., Horn, G., Herrmann, C., Scherer, A., McCormick, F., and Wittinghofer, A. (1995). Nature (London) 375, 554–560.
Nemethy, G., Pottle, M. S., and Scheraga, H. A. (1983). J. Phys. Chem. 87, 1883–1887.
Pincus, M. R. and Brandt-Rauf, P. W. (1985). Proc. Natl. Acad. Sci. USA 82, 3596–3600.
Pincus, M. R., Brandt-Rauf, P. W., Gibson, K., Carty, R. P., Lubowsky, J., Avitable, M., and Scheraga, H. A. (1987). Proc. Natl. Acad. Sci. USA 89, 8375–8379.
Pincus, M. R., Brandt-Rauf, P. W., Michl, J., and Friedman, F. K. (2000). Cancer Invest. 18, 39–50.
Poullet, P., Lin, B., Esson, K., and Tamanoi, F. (1994). Mol. Cell Biol. 14, 815-.
Ranginwale, M., Smith, S., Flom, J., Chie, L., Kanovsky, M., Chung, D., Friedman, F. K., Robinson, R. C., Brandt-Rauf, P. W., Yamaizumi, Z., Michl, J., and Pincus, M. R. (2001). Exp. Cell Res. 269, 162–169.
Rodriguez-Viciana, P., Warne, P. H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M. J., Waterfield, M. D., and Downward, J. (1994). Nature (London) 370, 527–532.
Scheffzek, K., Ahmadian, M. R., Kabsch, W., Weismuller, L., Lautwein-Schmitz, F., and Wittinghofer, A. (1997). Science 227, 333–338.
Weiner, S. J., Kollman, P. A., Case, D. A., Singh, V. C., Ghio, C., Alagona, G., Profeta, S., and Weiner, P. K. (1986). J. Am. Chem. Soc. 106, 765–784.
Yang, J.-Y. and Widmann, C. (2001). Mol. Cell. Biol. 21, 5346–5358.
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Chen, J.M., Friedman, F.K., Brandt-Rauf, P.W. et al. Comparison of the Average Structures, from Molecular Dynamics, of Complexes of GTPase Activating Protein (GAP) with Oncogenic and Wild-Type ras-p21: Identification of Potential Effector Domains. J Protein Chem 21, 349–359 (2002). https://doi.org/10.1023/A:1019994302273
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DOI: https://doi.org/10.1023/A:1019994302273