Mutation of cytochrome c in humans causes mild autosomal dominant thrombocytopenia. The role of cytochrome c in platelet formation, and the molecular mechanism underlying the association of cytochrome c mutations with thrombocytopenia remains unknown, although a gain-of-function is most likely. Cytochrome c contributes to several cellular processes, with an exchange between conformational states proposed to regulate changes in function. Here, we use experimental and computational approaches to determine whether pathogenic variants share changes in structure and function, and to understand how these changes might occur. Three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and peroxidase activity. Molecular dynamics simulations of these variants, and two non-naturally occurring variants (G41A, G41T), indicate that increased apoptosome activation correlates with the increased overall flexibility of cytochrome c, particularly movement of the Ω loops. Crystal structures of Y48H and G41T complement these studies which overall suggest that the binding of cytochrome c to apoptotic protease activating factor-1 (Apaf-1) may involve an ‘induced fit’ mechanism which is enhanced in the more conformationally mobile variants. In contrast, peroxidase activity did not significantly correlate with protein dynamics. Thus, the mechanism by which the variants increase peroxidase activity is not related to the conformational dynamics of the native hexacoordinate state of cytochrome c. Recent molecular dynamics data proposing conformational mobility of specific cytochrome c regions underpins changes in reduction potential and alkaline transition pK was not fully supported. These data highlight that conformational dynamics of cytochrome c drive some but not all of its properties and activities.
Skip Nav Destination
Article navigation
February 2021
-
Cover Image
Cover Image
LRRK1 and LRRK2 are regulated by differing upstream signals and phosphorylate distinct Rab GTPases. You can read more about this in the article by Malik and colleagues (pp. 553–578) in this issue. Image provided by Dario R. Alessi.
Research Article|
February 12 2021
Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased apoptotic activity
Matthias Fellner;
Matthias Fellner
Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing
1Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
Search for other works by this author on:
Rinky Parakra;
Rinky Parakra
Investigation, Methodology, Writing - original draft
1Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
Search for other works by this author on:
Kirstin O. McDonald;
Kirstin O. McDonald
Investigation, Writing - original draft
1Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
Search for other works by this author on:
Itamar Kass;
Itamar Kass
*
Data curation, Software, Writing - review & editing
2Department of Biochemistry and Molecular Biology and Victorian Life Sciences Computation Initiative Life Sciences Computation Centre, Monash University, Clayton, Victoria 3800, Australia
Search for other works by this author on:
Guy N.L. Jameson;
Guy N.L. Jameson
Conceptualization, Resources, Formal analysis, Supervision, Writing - original draft, Writing - review & editing
3School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia
Search for other works by this author on:
Sigurd M. Wilbanks;
Sigurd M. Wilbanks
Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Methodology, Writing - original draft, Writing - review & editing
1Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
Search for other works by this author on:
Elizabeth C. Ledgerwood
Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Methodology, Writing - original draft, Project administration, Writing - review & editing
1Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
Correspondence: Elizabeth Ledgerwood (liz.ledgerwood@otago.ac.nz)
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
October 11 2020
Revision Received:
January 17 2021
Accepted:
January 21 2021
Accepted Manuscript online:
January 22 2021
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2021
Biochem J (2021) 478 (3): 669–684.
Article history
Received:
October 11 2020
Revision Received:
January 17 2021
Accepted:
January 21 2021
Accepted Manuscript online:
January 22 2021
Citation
Matthias Fellner, Rinky Parakra, Kirstin O. McDonald, Itamar Kass, Guy N.L. Jameson, Sigurd M. Wilbanks, Elizabeth C. Ledgerwood; Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased apoptotic activity. Biochem J 12 February 2021; 478 (3): 669–684. doi: https://doi.org/10.1042/BCJ20200793
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.