Structural Characterization of Cardiolipin-Driven Activation of Cytochrome C into a Peroxidase and Membrane Perturbation

Details

• Personal Author:
  Kagan VE ; Kapralov AA ; Klein-Seetharaman J ; Mohammadyani D ; Nuar N ; Planas-Iglesias J ; Samhan Arias AK ; Sanghera N ; Stepanov G ; Yanamala N
• Description:
  The interaction between CL and cytochrome c (cyt-c), results in a gain of function of peroxidase activity by cyt-c. Despite intensive research, disagreements on nature and molecular details of this interaction remain. In particular, it is still not known how the interaction triggers the onset of apoptosis. Enzymatic characterization of peroxidase activity has highlighted the need for a critical threshold concentration of CL, a finding of profound physiological relevance in vivo. Using solution NMR, fluorescence spectroscopy, and in silico modeling approaches we here confirm that full binding of cyt-c to the membrane requires a CL:cyt-c threshold ratio of 5:1. Among three binding sites, the simultaneous binding of two sites, at two opposing sides of the heme, provides a mechanism to open the heme crevice to substrates, resulting in "productive binding" in which cyt-c then sequesters CL, inducing curvature in the membrane. Membrane perturbation along with lipid peroxidation, due to interactions of heme/CL acyl chains, initiates the next step in the apoptotic pathway of making the membrane leaky. The third CL binding site while allowing interaction with the membrane, does not cluster CL or induce subsequent events, making this interaction "unproductive". [Description provided by NIOSH]
• Subjects:
  Cytology Energy Metabolism Enzymes Ferrous Compounds Lipids Occupational Health Porphyrins Safety
• Keywords:
  Apoptosis Author Keywords: Protein-lipid Interactions Biochemical Markers Bioenergetics Biophysics Cell Biology Cell Damage Cell Death Cell Function Cell Migration Cell Signaling Cellular Function Cellular Structures Cellular Transport Mechanism Chemical Binding Coarse Grained Simulation Conformational Changes Electrostatic Fields Enzymatic Effects In Vivo Study Iron Lipid Peroxidation Membrane Dysfunction Molecular Signaling Oxidation Peroxidases Phospholipids Proteins

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• ISSN:
  0005-2736
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Maryland ; OSHA Region 3 ; Pennsylvania ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  1860
• Issue:
  5
• NIOSHTIC Number:
  nn:20050932
• Citation:
  Biochim Biophys Acta, Biomembranes 2018 May; 1860(5):1057-1068
• Contact Point Address:
  Judith Klein-Seetharaman, Professor, Division of Metabolic and Vascular Health, Medical School, University of Warwick, Coventry CV4 7AL, UK
• Email:
  J.Klein-Seetharaman@warwick.ac.uk
• Federal Fiscal Year:
  2018
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Biochimica et Biophysica Acta - Biomembranes
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:049c3520b11cb684740a77be46949de54c880f463b09c6b137975b8623c7dda7a30f8af588e9340b213e1b280a4e523996a783e30e46ca0650cfe77010ec0fa5
• Download URL:
  https://stacks.cdc.gov/view/cdc/211111/cdc_211111_DS1.pdf
• File Type:
  [PDF - 2.43 MB ]