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Functional mimicry of proteins by cell-penetrating peptides

Cell-penetrating peptides (CPPs) have proven themselves as valuable vectors for intracellular delivery. Relatively little is known about the frequency of cell-penetrating sequences in native proteins and their functional role. By computational comparison of peptide sequences, we predicted that intracellular loops of G-protein coupled receptors (GPCR) have high probability for occurrence of cell-penetrating motifs. Since the loops are also receptor and G-protein interaction sites, we postulated that the short CPPs, derived from GPCR, when applied extra-cellularly can pass the membrane and modulate G-protein activity similarly to parent receptor proteins.

Two model systems were analysed as proofs of the principle. A peptide called M511, based on the C-terminal intracellular sequence of the rat angiotensin receptor (AT1AR) internalized into live cells and elicited blood vessel contraction even in the presence of AT1AR antagonist. M511 interacted with the same selectivity towards G-protein subtypes as agonist-activated AT1AR and blockade of phospholipase C abolished its effect. Another CPP, G53-2, derived from human glucagon-like peptide receptor (GLP-1R) induced insulin release from isolated pancreatic islets. The mechanism was again found to be shared with the original GLP-1R, namely G11-mediated inositol 1,4,5-triphosphate release pathway. These data reveal a novel possibility to mimic the effects of signalling transmembrane proteins by application of shorter peptide fragments.

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