Tumor promoter binding of the protein kinase C C1 homology domain peptides of RasGRPs, chimaerins, and Unc13s.

Kazuhiro Irie, Akiko Masuda, Mayumi Shindo, Yu Nakagawa, Hajime Ohigashi

Index: Bioorg. Med. Chem. 12(17) , 4575-83, (2004)

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Abstract

Recent investigations discovered nonkinase-type phorbol ester receptors, RasGRPs, chimaerins, and Unc13s. Phorbol ester binding occurs at the cysteine-rich sequences of about 50 residues in the C1 domains of these receptors. Fifty-one-residue RasGRP C1 peptides except for RasGRP2 showed significant phorbol 12,13-dibutyrate (PDBu) binding, but the K(d) values of the RasGRP1 and RasGRP3 C1 peptides were about 10-fold larger than those for the corresponding whole enzymes. Addition of the C-terminal basic amino acid cluster decreased their K(d) values about 10-fold, suggesting that the positive charges of these C1 peptides play an important role in the PDBu binding in the presence of negatively-charged phosphatidylserine. The 51-mer chimaerin C1 peptides showed potent PDBu binding, while the Unc13 and Munc13-1 C1 peptides without sufficient positive charges hardly bound PDBu. By the rapid screening system using this C1 peptide library, 5-prenyl-indolactam-V was identified as a promising lead for the novel protein kinase C isozyme specific ligands.