Eukaryote protein kinase domains segregate into two large groups, phosphorylating either serine/threonine or tyrosine residues on target proteins. However, both groups have essentially similar three-dimensional structures comprised of two lobes with the active site located in the cleft between the small and large lobes [4,5]. The smaller, N-terminal (N-)
lobe contains mainly beta structures and one important helix termed helix C, whereas the C-terminal (C-) lobe is largely alpha-helical. Important structural motifs include the glycine-rich motif that forms a phosphate-binding (P-) loop that anchors the ATP phosphates; the activation loop, often containing phosphorylation sites, provides a surface for peptide substrate binding (Fig. 1).
All protein kinases catalyze the same reaction—the transfer of the gamma-phosphate from ATP to the hydroxyl group of a Ser, Thr, or Tyr—and adopt strikingly similar structures in their active forms. The active structure positions the substrates within the constellation of catalytic residues. By contrast, the mechanisms used to maintain protein kinases in inactive forms show remarkable diversity. These range from allosteric to intrasteric and everything in between  and are used to modulate the conformations of the activation loop and the P-loop, the position of helix C, the access to ATP and substrate binding sites, and the relative orientation of the two lobes (Figs. 1 and 2). The control can be exerted by internal regions of the kinase catalytic domains, by sequences outside the catalytic domain, or by additional subunits or interacting proteins; these regions or proteins may respond to second messengers, and their expression may be controlled by the functional state of the cell. They can target the kinase to different substrates or subcellular locations or inhibit the kinase activity. These possible regulatory sites affect each other, resulting in a rich spectrum of possible regulatory pathways. We first review allosteric and intrasteric behaviors in protein kinases, and then address how individual sites are regulated.
Copyright © 2003, Elsevier Science (USA).
Handbook of Cell Signaling, Volume 1 539 All rights reserved.
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