Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2192332 | Journal of Molecular and Cellular Cardiology | 2007 | 7 Pages |
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 ÏRACK peptides, derived from a sequence within each PKC with high homology to its respective RACK. We noted that all the ÏRACK 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 ÏRACK sequence. We focused on εPKC ÏRACK peptide, where the pseudo-εRACK sequence (ÏεRACK; HDAPIGYD; corresponding to εPKC85-92) is different in charge from the homologous RACK-derived sequence (NNVALGYD; corresponding to εRACK285-292) in the second amino acid. Here we show that changing the charge of the ÏεRACK 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.
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Authors
Tamar Liron, Leon E. Chen, Hanita Khaner, Alice Vallentin, Daria Mochly-Rosen,