Switching Src with RNA

Src family tyrosine kinases mediate signal transduction cascades through two functional states. In its inactive state, the SH2 domain of c-Src binds to an intramolecular phosphotyrosine near the C terminus of the protein. In the cell, kinase activity can be switched on by dephosphorylation of the key tyrosine residue. Proteins, small molecules and synthetic phosphopeptides also can relieve kinase inhibition in trans by targeting the Src SH2 domain. Röglin et al. now report the design of a phosphopeptide– nucleic acid conjugate that can regulate Src kinase activity by reversible hybridization with complementary DNA or RNA. To create Src kinase activators, the authors synthesized peptide–nucleic acid conjugates in which a Src-specific phosphopeptide (pSrc) was flanked by two short sequences of peptide nucleic acid (PNA). Hybridization of the PNA segments with a complementary nucleic acid (PNA, DNA or RNA) changed the conformation of the embedded peptide and altered its binding affinity for the Src SH2. Hybridization of a PNA-pSrc conjugate with a short complementary DNA sequence forced the pSrc peptide into a lowaffinity Src-binding conformer. This conjugate could be converted into a high-affinity Src ligand that triggered kinase activation by the addition of a complementary RNA or DNA. These studies open up the possibility that small cellular RNAs could be hijacked to endow synthetic peptide–nucleic acid conjugates with protein targeting functions. (Chembiochem 10, 758–765, 2009) TLS