Rational design of a selective antagonist of epsilon protein kinase C derived from the selective allosteric agonist, pseudo-RACK peptide.

Abstract:

:We have previously shown that domains involved in binding of protein kinase C (PKC) isozymes to their respective anchoring proteins (RACKs) and short peptides derived from these domains are PKC isozyme-selective antagonists. We also identified PKC isozyme-selective agonists, named psiRACK peptides, derived from a sequence within each PKC with high homology to its respective RACK. We noted that all the psiRACK sequences within each PKC isozyme have at least one non-homologous amino acid difference from their corresponding RACK that constitutes a charge change. Based on this information, we have devised here a new approach to design an isozyme-selective PKC antagonist, derived from the psiRACK sequence. We focused on epsilonPKC psiRACK peptide, where the pseudo-epsilonRACK sequence (psiepsilonRACK; HDAPIGYD; corresponding to epsilonPKC85-92) is different in charge from the homologous RACK-derived sequence (NNVALGYD; corresponding to epsilonRACK285-292) in the second amino acid. Here we show that changing the charge of the psiepsilonRACK peptide through a substitution of only one amino acid (aspartate to asparagine) resulted in a peptide with an opposite activity on the same cell function and a substitution for aspartate with an alanine resulted in an inactive peptide. These data support our hypothesis regarding the mechanism by which pseudo-RACK peptide activates PKC in heart cells and suggest that this approach is applicable to other signaling proteins with inducible protein-protein interactions.

journal_name

J Mol Cell Cardiol

authors

Liron T,Chen LE,Khaner H,Vallentin A,Mochly-Rosen D

doi

10.1016/j.yjmcc.2007.01.007

subject

Has Abstract

pub_date

2007-04-01 00:00:00

pages

835-41

issue

4

eissn

0022-2828

issn

1095-8584

pii

S0022-2828(07)00009-0

journal_volume

42

pub_type

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