Cytochrome c binds cardiolipin on the concave surface of the inner mitochondrial membrane, before oxidizing the lipid and initiating the apoptotic pathway. This interaction has been studied in vitro, where mimicking the membrane curvature of the binding environment is difficult. Here we report binding to concave, cardiolipin-containing, membrane surfaces and compare findings to convex binding under the same conditions. For binding to the convex outer surface of cardiolipin-containing vesicles, a two-step structural rearrangement is observed with a small rearrangement detectable by Soret circular dichroism (CD) occurring at an exposed lipid-toprotein ratio (LPR) near 10 and partial unfolding detectable by Trp59 fluorescence occurring at an exposed LPR near 23. On the concave inner surface of cardiolipin-containing vesicles, the structural transitions monitored by Soret CD and Trp59 fluorescence are coincident and occur at an exposed LPR near 58. On the concave inner surface of mitochondrial cristae, we estimate the LPR of cardiolipin to cytochrome c is between 50 and 100. Thus, cytochrome c may have adapted to its native environment so that it can undergo a conformational change that switches on its peroxidase activity when it binds to CLcontaining membranes in the cristae early in apoptosis. Our results show that membrane curvature qualitatively affects peripheral protein−lipid interactions and also highlights the disparity between in vitro binding studies and their physiological counterparts where cone-shaped lipids, like cardiolipin, are involved.
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