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

Bioorganic & Medicinal Chemistry
K IrieHajime Ohigashi

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.

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Citations

Jul 26, 2005·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Kazuhiro IrieHajime Ohigashi
Mar 27, 2007·Nature Reviews. Cancer·Erin M Griner, Marcelo G Kazanietz
Oct 2, 2015·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Lucia Stefanini, Wolfgang Bergmeier
Nov 7, 2014·Chemical Reviews·Joydip Das, Ghazi M Rahman
Mar 29, 2014·Chemical Record : an Official Publication of the Chemical Society of Japan ... [et Al.]·Kazuhiro Irie, Ryo C Yanagita
Jun 5, 2018·Platelets·Lucia Stefanini, Wolfgang Bergmeier
May 26, 2007·The Biochemical Journal·Joanne E JohnsonRobert J Kay
Oct 21, 2006·Biochemical Society Transactions·J C Stone
Jan 23, 2020·Science Signaling·Alexander P ByeMartyn P Mahaut-Smith
Mar 12, 2010·Platelets·Lucia Stefanini, Wolfgang Bergmeier
Jun 28, 2019·Biochemistry·Francisco A BlancoJoydip Das
Feb 6, 2008·Cellular Signalling·María José CalocaXosé R Bustelo

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