Conotoxin Phi-MiXXVIIA from the Superfamily G2 Employs a Novel Cysteine Framework that Mimics Granulin and Displays Anti-Apoptotic Activity

摘要

Conotoxins are a large family of disulfide-rich peptides that contain unique cysteine frameworks that target a broad range of ion channels and receptors. We recently discovered the 33-residue conotoxin Phi-MiXXVIIA from Conus miles with a novel cysteine framework comprising three consecutive cysteine residues and four disulfide bonds. Regioselective chemical synthesis helped decipher the disulfide bond connectivity and the structure of Phi-MiXXVIIA was determined by NMR spectroscopy. The 3D structure displays a unique topology containing two beta-hairpins that resemble the N-terminal domain of granulin. Similar to granulin, Phi-MiXXVIIA promotes cell proliferation (EC50 17.85 mu m) while inhibiting apoptosis (EC50 2.2 mu m). Additional frame-work XXVII sequences were discovered with homologous signal peptides that define the new conotoxin superfamily G2. The novel structure and biological activity of Phi-MiXXVIIA expands the repertoire of disulfide-rich conotoxins that recognize mammalian receptors.