Protein Engineering vol. 7 no. 2 pp. 243-257, 1994
© 1994 Oxford University Press
RESEARCH-ARTICLE |
Mutational analysis supports a structural model for the cell cycle protein kinase p34
Laboratory of Molecular Biophysics, Oxford University South Parks Road, Oxford OX1 3QU, UK 2Department of Microbiology, Oxford University South Parks Road, Oxford OX1 3QU, UK
1To whom correspondence should be addressed
Structural models for the eukaryotic cell cycle control protein p34 from human, S.pombe and S.cerevisiae have been derived from the crystallographic coordinates of the cAMP-dependent protein kinase (cAPK) catalytic subunit (active conformation) and compared with the structure of Inactive CDK2 apoenzyme. Differences between the p34 and cAPK catalytic sites provide a possible explanation for their different substrate specificities. The p34 models localize Tyrl5 and Thrl4 close to the sites of catalysis and substrate recognition where their phosphorylatlon could inhibit p34 kinase activity either by blocking MgATP or substrate binding. The conserved sequences PSTAIRE and LYLIFEFL are both close to the catalytic site and accessible on the protein surface available to mediate interactions with other proteins. It is predicted that p34 has an active-site cleft composed almost entirely of sequences common to all protein kinases and sequences unique to the p34 protein family. Genetic and biochemical analyses of p34 have shown that it interacts extensively with a number of other proteins. The model allows the relative disposition of these sites of mutation to each other and to the sites of catalysis and substrate recognition to be appreciated. Surface regions on p34 that are important for function have been identified. These sites identify residues that may interact with p13SUCL, cydin, plO7WEEL and p80cdc25
Keywords: cdc2/CDC28/cell cycle/molecular modelling/p34 protein kinase
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