A Conformational Switch to β-Sheet Structure in Cytochrome c Leads to Heme Exposure. Implications for Cardiolipin Peroxidation and Apoptosis

摘要

We report resonance Raman (RR) spectroscopic evidence for a hitherto unrecognized conformational transition to β-sheet structure in cytochrome c (cyt c), which may have important functional consequences. In addition to its electron-transfer activity in mitochondria, cyt c plays a key role in apoptosis, and partial unfolding seems to be a critical element in the mechanism. Jemmerson et al. have observed that, in association with lipid vesicles, cyt c binds an antibody that recognizes an unfolded region around residue Pro44 and that the same response is seen in apoptotic cells. Belikova et al. report that binding to cardiolipin induces peroxidase activity in cyt c, producing cardiolipin hydroperoxides that are required for release of pro-apoptotic factors. It seems likely that this activity is triggered by changes in heme ligation when cyt c interacts with lipids. In addition to cardiolipin, oleic acid has been observed to destabilize the cyt c fold; the oleic acid effect can be partially reversed by ATP, a component of the apoptosome.