Proceedings of the National Academy of Sciences · 1992 · 79 citations · 34 references
Molecular RegulationMolecular BiologyCam Kinase IiRegulatory RegionCellular PhysiologyMolecular PharmacologySignaling PathwayProtein FoldingReceptor Tyrosine KinaseCellular Regulatory MechanismCell SignalingCam Binding DomainProtein FunctionMolecular PhysiologyPharmacologyCell BiologyProtein PhosphorylationSignal TransductionNatural SciencesPhysiologyIntrasteric InhibitionCellular BiochemistrySystems BiologyMedicine
A regulatory region involved in both autoinhibition and calmodulin (CaM) binding has previously been identified in the multifunctional Ca2+/CaM-dependent protein kinase (CaM kinase II). We have tested the role of various segments of the regulatory region in autoinhibition by the analysis of a series of truncation, substitution, and deletion mutants of the CaM kinase II alpha subunit (CaM kinase II alpha). Unexpectedly, the sequence Lys-Lys-Phe-Asn at positions 291-294, adjacent to the CaM binding domain, was found to be sufficient to maintain an inhibited state in a truncated form of the kinase. However, these residues are not essential in the context of the full-length protein, indicating the importance of additional residues from the overlapping CaM binding domain. We propose here a molecular model for CaM kinase II alpha based on the three-dimensional structure of the cAPK-PKI-(5-24) (protein kinase inhibitor fragment) complex. It is predicted from this model that autoinhibition is of the pseudosubstrate variety and that autophosphorylation of Thr-286 could occur by an intersubunit reaction in the holoenzyme complex.
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Solution structure of a calmodulin-target peptide complex by multidimensional NMR
Mitsuhiko Ikura, G. Marius Clore, Angela M. Gronenborn et al. · Science · 1992 · 1.3K citations