Interactions of cytochrome c (cyt c) with cardiolipin(CL)-rich mitochondrial membranes play an important role in early stages of apoptosis. Induced by these interactions, conformational changes in cyt c promote the peroxidase function of the protein, the activity that targets CL itself. Our fluorescence studies of multiple dye-labeled cyt c variants have revealed that the CL-bound species vary in degree of the polypeptide compactness and the heme exposure. Binding to the CL-rich membrane triggers losening of the cyt c structure, protein anchoring to the membrane, and ultimately the large-scale polypeptide unfolding on the membrane surface. Within these extended structures, heme misligation inhibits the cyt c peroxidase activity. When the membrane surface area is limited, the protein ensemble is more compact. Several mutants of cyt c were engineered to probe the effects of perturbation of the heme environment without the large-scale protein unfolding. Disruption of the intraprotein hydrogen-bonding network in cyt c opens the heme crevice to stimulate the intrinsic peroxidase activity but also globally destabilizes the protein yielding a higher fraction of extended structures in the CL-bound ensemble. The fluorescence studies are being extended to biological membranes where many of the same phenomena are observed.

Cytochrome c unfolding at cardiolipin-rich membrane surfaces

249th National Meeting (2015)

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