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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)
59 Downloads (Pure)

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