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

Structure (London, England : 1993) (2019-03-19)
Mingyue Li, Abhishek Mandal, Vladimir A Tyurin, Maria DeLucia, Jinwoo Ahn, Valerian E Kagan, Patrick C A van der Wel
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Diethylenetriaminepentaacetic acid, ≥99% (titration)
Sigma-Aldrich
Cytochrome c from equine heart, ≥95% based on Mol. Wt. 12,384 basis
Sigma-Aldrich
HEPES sodium salt, BioPerformance Certified, suitable for cell culture, ≥99.5%
Sigma-Aldrich
1,2-Dioleoyl-sn-glycero-3-phosphocholine, lyophilized powder
Sigma-Aldrich
5-Aminolevulinic acid hydrochloride, BioReagent, suitable for cell culture, powder, ≥98%
Supelco
ABC Vial, 2 mL (vial only), 9 mm thread, clear glass vial (with marking spot), pkg of 1000 ea