Zebrafish as a model for cardiac disease; Cryo-EM structure of native cardiac thin filaments from Danio Rerio

Marston Bradshaw, John M Squire, Edward Morris, Georgia G Atkinson, Rebecca Richardson, Jon G Lees, Massimo Caputo, Maria Giulia Bigotti, Danielle M Paul*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

1 Citation (Scopus)

Abstract

Actin, tropomyosin and troponin, the proteins that comprise the contractile apparatus of the cardiac thin filament, are highly conserved across species. We have used cryo-EM to study the three-dimensional structure of the zebrafish cardiac thin and actin filaments. With 70% of human genes having an obvious zebrafish orthologue, and conservation of 85% of disease-causing genes, zebrafish are a good animal model for the study of human disease. Our structure of the zebrafish thin filament reveals the molecular interactions between the constituent proteins, showing that the fundamental organisation of the complex is the same as that reported in the human reconstituted thin filament. A reconstruction of zebrafish cardiac F-actin demonstrates no deviations from human cardiac actin over an extended length of 14 actin subunits. Modelling zebrafish homology models into our maps enabled us to compare, in detail, the similarity with human models. The structural similarities of troponin-T in particular, a region known to contain a hypertrophic cardiomyopathy ‘hotspot’, confirm the suitability of zebrafish to study these disease-causing mutations.
Original languageEnglish
Pages (from-to)179-192
Number of pages14
JournalJournal of Muscle Research and Cell Motility
Volume44
Issue number3
Early online date22 Jul 2023
DOIs
Publication statusPublished - 1 Sept 2023

Bibliographical note

Funding Information:
DP acknowledges support from the British Heart Foundation (FS/14/18/3071), The Alan Turing Institute and the Academy of Medical Sciences (SBF003\1142). MB is supported by the British Heart Foundation on a PhD Studentship FS/20/5/34973 supervised by DP & MC. The authors gratefully acknowledge access and support of the Wolfson Bioimaging Facility and the GW4 Facility for High-resolution Electron Cryo-Microscopy, funded by the Wellcome Trust (202904/Z/16/Z and 206181/Z/17/Z) and BBSRC (BB/R000484/1). We acknowledge Diamond Light Source for access and support of the cryo-EM facilities at the UK’s national Electron Bio-imaging Centre (eBIC) [under proposal EM 32707], funded by the Wellcome Trust, MRC and BBSRC.

Publisher Copyright:
© 2023, The Author(s).

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