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Novel determinant of PKC- anchoring at cardiac Z-lines

Department of Physiology, University of Wisconsin, Madison, Wisconsin

Submitted 2 November 2004 ; accepted in final form 7 June 2005

The Z-line represents a critical link between the transverse tubule network and cytoskeleton of cardiac cells with a role in anchoring structural proteins, ion channels, and signaling molecules. Protein kinase C- (PKC-) regulates cardiac excitability, cardioprotection, and growth, possibly as a consequence of translocation to the Z-line/T tubule region. To investigate the mechanism of PKC- translocation, fragments of its NH₂-terminal 144-amino acid variable domain, V1, were fused with green fluorescent protein and evaluated by quantitative Fourier image analysis of decorated myocytes. Deletion of 23 amino acids from the NH₂-terminus of V1, including an EAVSLKPT motif important for binding to a receptor for activated C kinase (RACK2), reduced but did not abolish Z-line binding. Further deletions of up to 84 amino acids from the NH₂-terminus of V1 also did not prevent Z-line decoration. However, deletions of residues 85–144 from the COOH-terminus strongly reduced Z-line binding. COOH-terminal deletions caused 2.5-fold greater loss of binding energy (G) than did NH₂-terminal deletions. Synthetic peptides derived from these regions modulated V1 binding and cardiac myocyte function, but also revealed considerable heterogeneity within populations of adult cardiac myocytes. The COOH-terminal subdomain important for Z-line anchoring maps to a surface in the V1 crystal structure that complements the eight-amino acid RACK2 binding site and two previously identified membrane docking motifs. PKC- anchoring at the cardiac Z-line/T tubule appears to rely on multiple points of contact probably involving protein-lipid and protein-protein interactions.

protein kinase C-

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