Inhibition of the cAMP-dependent protein kinase by synthetic A-helix peptides.
The catalytic subunit of the cAMP-dependent protein kinase from Dictyostelium discoideum, PkaC, displays the same properties as its mammalian counterpart, except for being about twice as large in size. Sequence comparisons indicated the presence of a conserved alpha-helix (A-helix) within the N-terminal region of PkaC which could potentially establish close contacts with the catalytic core [Véron, M., et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 10618-10622]. We show in this report that a synthetic peptide with the A-helix sequence inhibits PKA activity, whereas unrelated peptides display no inhibitory activity. The inhibition seems competitive with respect to the kemptide substrate rather than due to binding to a secondary site. We further show by amino acid replacements that the last lysine of the A-helix sequence is involved in this specific inhibition. A model is proposed for the possible role of the A-helix.
Institut de biologie cellulaire et de morphologie, Lausanne, Switzerland.
S
S
Gamboni
C
C
Chaperon
K
K
Friedrich
P J
PJ
Baehler
C D
CD
Reymond
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002942:Circular Dichroism; D017124:Conserved Sequence; D003460:Crystallization; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D004023:Dictyostelium / Q000201:enzymology; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
D000596:Amino Acids; D009842:Oligopeptides; D017868:Cyclic AMP-Dependent Protein Kinases