[PDF][PDF] Surface-binding to cardiolipin nanodomains triggers cytochrome c pro-apoptotic peroxidase activity via localized dynamics

M Li, A Mandal, VA Tyurin, M DeLucia, J Ahn… - Structure, 2019 - cell.com
M Li, A Mandal, VA Tyurin, M DeLucia, J Ahn, VE Kagan, PCA van der Wel
Structure, 2019cell.com
The peroxidation of cardiolipins by reactive oxygen species, which is regulated and
enhanced by cytochrome c (cyt c), is a critical signaling event in mitochondrial apoptosis. We
probe the molecular underpinnings of this mitochondrial death signal through structural and
functional studies of horse heart cyt c binding to mixed-lipid membranes containing
cardiolipin with mono-and polyunsaturated acyl chains. Lipidomics reveal the selective
oxidation of polyunsaturated fatty acid (PUFA) cardiolipin (CL), while multidimensional solid …
Summary
The peroxidation of cardiolipins by reactive oxygen species, which is regulated and enhanced by cytochrome c (cyt c), is a critical signaling event in mitochondrial apoptosis. We probe the molecular underpinnings of this mitochondrial death signal through structural and functional studies of horse heart cyt c binding to mixed-lipid membranes containing cardiolipin with mono- and polyunsaturated acyl chains. Lipidomics reveal the selective oxidation of polyunsaturated fatty acid (PUFA) cardiolipin (CL), while multidimensional solid-state NMR probes the structure and dynamics of the membrane and the peripherally bound protein. The hydrophilic milieu at the membrane interface stabilizes a native-like fold, but also leads to localized flexibility at the membrane-interacting protein face. PUFA CL acts as both a preferred substrate and a dynamic regulator by affecting the dynamics of the cyt c N70-I85 Ω loop, which covers the heme cavity.
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