Plasma membrane localization of myristoylated c-Src, a proto-oncogene protein-tyrosine kinase, is required for its signaling activity. Recent studies proposed that UNC119 protein functions as a solubilizing factor for myristoylated proteins, thereby regulating their subcellular distribution and signaling. The underlying molecular mechanism by which UNC119 regulates the membrane binding of c-Src has remained elusive. By combining different biophysical techniques, we have found that binding of a myristoylated c-Src-derived N-terminal peptide (Myr-Src) by UNC119A results in a reduced membrane binding affinity of the peptide, due to the competition of binding to membranes. The dissociation of Myr-Src from membranes is facilitated in the presence of UNC119A, as a consequence of which the clustering propensity of this peptide on the membrane is partially impaired. By these means, UNC119A is able to regulate c-Src spatially in the cytoplasm and on cellular membranes, and this has important implications for its cellular signaling.
Keywords: FRET; lipopeptides; myristoylation; protein-tyrosine kinases; vesicles.
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