Protein Kinases Specificity

Since the determinants of protein kinase specificity involve complex 3-dimensional interactions, these motifs, short amino-acid sequences describing the primary structure around the phosphoacceptor residue, are a significant oversimplification of the issue. They do not take into account possible secondary and tertiary structural elements, or determinants from other polypeptide chains or from distant locations within the same chain. Furthermore, not all of the residues described in a particular specificity motif may carry the same weight in determining recognition and phosphorylation by the kinase. As a consequence, they should be used with some caution.

On the other hand, many of the residues within these consensus sequences have in fact proven to be crucial recognition elements, and the very simplicity of these motifs has made them useful in the study of protein kinases and their substrates. In addition to the prediction of phosphorylation sites, short synthetic oligopeptides based on consensus motifs are often excellent substrates for protein kinase activity assays.

Some protein kinases such as CKI and GSK-3 contain phosphoamino acid residues in their recognition motifs, and have been termed "hierarchical" protein kinases [see (3) for review]. They often require prior phosphorylation by another kinase at a residue in the vicinity of their own phosphorylation site. S(P) represents such preexisting phosphoserine residues.

(1) Kennelly, P. J., and Krebs, E. G. (1991) J. Biol. Chem. 266, 15555–15558. PMID: 1651913
(2) Pearson, R. B., and Kemp, B. E. (1991). In T. Hunter and B. M. Sefton (Eds.), Methods in Enzymology Vol. 200, (pp. 62–81). San Diego: Academic Press.
(3) Roach, P. J. (1991) J. Biol. Chem. 266, 14139–14142. PMID: 1650349
(4) Flotow, H. et al. (1990) J. Biol. Chem. 265, 14264–14269. PMID: 2117608
(5) Russo, G. L. et al. (1992) J. Biol. Chem. 267, 20317–20325. PMID: 1400350
(6) Fiol, C. J. et al. (1990) J. Biol. Chem. 265, 6061–6065. PMID: 2156841
(7) Davis, R. J. (1993) J. Biol. Chem. 268, 14553–14556. PMID: 8325833
(8) Songyang, Z. et al. (1995) Nature 373, 536–539. PMID: 7845468
(9) Geahlen, R. L. and Harrison, M. L. (1990). In B. E. Kemp (Ed.), Peptides and Protein Phosphorylation, (pp. 239–253). Boca Raton: CRC Press.
(10) Stevenson, L.M. et al. (2003) J. Biol. Chem. 278, 50956–50960. PMID: 14506259