Abstract
PROTEIN phosphorylation by protein kinases plays a central regulatory role in cellular processes and these kinases are themselves tightly regulated1. One common mechanism of regulation involves Ca2+-binding proteins (CaBP) such as calmodu-lin (CaM)2. Here we report a Ca2+-effector mechanism for protein kinase activation by demonstrating the specific and > 1,000-fold activation of the myosin-associated giant protein kinase twitchin by Ca2+/S100Al2. S100A12 is a member of a large CaBP family that is implicated in various cellular processes, including cell growth, differentiation and motility, but whose molecular actions are largely unknown3. The S100Al2-binding site is a part of the autoregulatory sequence positioned in the active site that is responsible for intrasteric autoinhibition of twitchin kinase; the mechanism of autoinhibition based on the crystal structures of two twitchin kinase fragments is described elsewhere4. Ca2+/S100 represents a likely physiological activator for the entire family of giant protein kinases involved in muscle contractions and cyto-skeletal structure2,5–9.
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References
Kemp, B. E. et al. in Protein Kinases (ed. Woodgett, J. R.) 30–67 (IRL, Oxford, 1994).
Strynadka, N. C. J. & James, M. N. G. A. Rev. Biochem. 58, 951–998 (1989).
Zimmer, D. B., Cornwall, E. H., Landar, A. & Song, W. Brain Res. Bull. 37, 417–429 (1995).
Kobe, B. et al. Nature struct Biol. (submitted).
Benian, G. M., Kiff, J. E., Neckleman, N., Moerman, D. G. & Waterston, R. H. Nature 342, 45–50 (1989).
Labeit, S. & Kolmerer, B. Science 270, 293–296 (1995).
Moerman, D. G., Benian, G. M., Barstead, R. J., Schriefer, L. A. & Waterston, R. H. Genes Dev. 2, 93–105 (1988).
Ayme-Southgate, A., Southgate, R., Saide, J., Benian, G. M. & Pardue, M. L. J. Cell Biol. 128, 393–403 (1995).
Probst, W. C. et al. Proc. natn. Acad. Sci. U.S.A. 91, 8487–8491 (1994).
Hu, S.-H. et al. Nature 369, 581–584 (1994).
Heierhorst, J., Probst, W. C., Kohanski, R. A., Buku, A. & Weiss, K. R. Eur. J. Biochem. 233, 426–431 (1995).
Heierhorst, J., Probst, W. C., Vilim, F. S. ; Buku, A. & Weiss, K. R. J. biol. Chem. 269, 21086–21093 (1994).
Gautel, M., Castiglione Morelli, M. A., Pfuhl, M., Motta, A. & Pastore, A. Eur. J. Biochem. 230, 752–759 (1995).
Lei, J., Tang, X., Chamber, T. C., Pohl, J. & Benian, G. M. J. biol. Chem. 269, 21078–21085 (1994).
Kato, K., Kimura, S., Haimoto, H. & Suzuki, F. J. Neurochem. 46, 15555–1560 (1986).
Schäfer, B. W., Wicki, R., Engelkamp, D., Mattei, M.-G. & Heizmann, C. W. Genomics 25, 638–643 (1995).
Baudier, J., Glasser, N. & Gerard, D. J. biol. Chem. 261, 8192–8203 (1986).
Taylor, S. S. & Radzio-Andzelm, E. in Protein Kinases (ed. Woodgett, J. R.) 1–29 (IRL, Oxford, 1994).
Ikura, M. et al. Science 256, 632–638 (1992).
Meador, W. E., Means, A. R. & Quiocho, F. A. Science 257, 1251–1255 (1992).
Meador, W. E., Means, A. R. & Quiocho, F. A. Science 262, 1718–1721 (1993).
Potts, B. C. M. et al. Nature struct. Biol. 2, 790–796 (1995).
Babu, Y. S. et al. Nature 315, 37–40 (1985).
Escobar, A. L., Monck, J. R., Fernandez, J. M. & Vergara, J. L. Nature 367, 739–741 (1994).
Nicholls, A., Sharp, K. A. & Honig, B. Proteins 11, 281–296 (1991).
Lawrence, M. C. & Colman, P. M. J. molec. Biol. 234, 946–950 (1993).
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Heierhorst, J., Kobe, B., Feil, S. et al. Ca2+ /S100 regulation of giant protein kinases. Nature 380, 636–639 (1996). https://doi.org/10.1038/380636a0
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DOI: https://doi.org/10.1038/380636a0
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