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

Mingyue Li, Abhishek Mandal, Vladimir A. Tyurin, Maria DeLucia, Jinwoo Ahn, Valerian E. Kagan, Patrick C. A. van der Wel*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

31 Citaten (Scopus)
149 Downloads (Pure)

Samenvatting

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.
Originele taal-2English
Pagina's (van-tot)806-815.e4
Aantal pagina's15
TijdschriftStructure
Volume27
Nummer van het tijdschrift5
Vroegere onlinedatum14-mrt.-2019
DOI's
StatusPublished - 7-mei-2019

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