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Surface-Binding to Cardiolipin Nanodomains Triggers Cytochrome c Pro-apoptotic Peroxidase Activity via Localized Dynamics

Li, M., Mandal, A., Tyurin, V. A., DeLucia, M., Ahn, J., Kagan, V. E. & van der Wel, P. C. A., 7-May-2019, In : Structure. 27, 5, p. 806-815.e4 15 p.

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DOI

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.
Original languageEnglish
Pages (from-to)806-815.e4
Number of pages15
JournalStructure
Volume27
Issue number5
Early online date14-Mar-2019
Publication statusPublished - 7-May-2019

    Keywords

  • cytochrome, cardiolipin, mitochondrial protein, apoptosis, membrane protein, PUFA, protein structure and dynamics, membrane oxidation, lipidomics, solid-state NMR, FERRICYTOCHROME-C, NATIVE-LIKE, NMR, MITOCHONDRIA, MEMBRANES, PROTEINS, TRANSITIONS, COEXISTENCE, INHIBITORS, RESOLUTION
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