title: Did protein kinase regulatory mechanisms evolve through elaboration of a simple structural component?
abstract: Statistical analysis of the functional constraints acting on eukaryotic protein kinases (EPKs) and on distantly related kinases suggests that EPK regulatory mechanisms evolved around an ancient structural component whose most distinctive features include the HxD-motif adjoining the catalytic loop, the F-helix, an F-helix aspartate, and the DFG-motif adjoined to the activation loop. The HxD-histidine constitutes a convergence point for signal integration, as conserved interactions link it to key catalytic residues, to the F-helix aspartate, and to both ends of the DFG-motif. These and other conserved features appear to be associated with DFG conformational changes and with coordinated movements possibly associated with phosphate transfer and ADP release. The EPKs have acquired structural features that link this core component to likely substrate-interacting regions at either end of the F-helix (most notably involving an F-helix tryptophan) and to three regions undergoing conformational changes upon kinase activation: the activation segment, the C-helix, and the nucleotide-binding pocket.
authors.affiliation: Cold Spring Harbor Laboratory, 1 Bungtown Road, P.O. Box 100, Cold Spring Harbor, NY 11724, USA.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Kannan
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Neuwald
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D030562:Databases, Protein; D019143:Evolution, Molecular; D018698:Glutamic Acid / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008957:Models, Genetic; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014364:Tryptophan / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D014867:Water; D018698:Glutamic Acid; D014443:Tyrosine; D006639:Histidine; D000244:Adenosine Diphosphate; D014364:Tryptophan; D011494:Protein Kinases