Abstract
Determination of the molecular targets of natural products has had profound impacts on studies of complex cellular machinery. Natural products are often coevolved with proteins targets and thereby likely to exhibit high selectivity to the human counterparts of those targets. Here we report isolation of a selective protein target of aurilide, a potent cytotoxic marine natural product. The ability of aurilide at low concentrations to induce apoptosis in human cancer cells has encouraged a range of biological analyses. Nonetheless, its mechanism of action has remained unknown. To identify the target of this potent cytotoxic molecule, we biochemically isolated a selective aurilide -binding protein, prohibitin 1 (PHB1). Our mechanistic analyses indicate that the interaction of aurilide with PHB1 in mitochondria activates the proteolytic processing of optic atrophy 1 (OPA1), leading to mitochondrial fragmentation and apoptosis.
