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

doi:10.1007/s10974-023-09653-5

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 journal › Article (Academic Journal) › peer-review

2 Citations (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 language	English
Pages (from-to)	179-192
Number of pages	14
Journal	Journal of Muscle Research and Cell Motility
Volume	44
Issue number	3
Early online date	22 Jul 2023
DOIs	https://doi.org/10.1007/s10974-023-09653-5
Publication status	Published - 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).

Access to Document

10.1007/s10974-023-09653-5Licence: CC BY

Handle.net

Persistent link

HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities
Alam, S. R. (Manager), Williams, D. A. G. (Manager), Eccleston, P. E. (Manager) & Greene, D. (Manager)
Facility/equipment: Facility
Research Data Storage Facility (RDSF)
Alam, S. R. (Manager), Williams, D. A. G. (Manager) & Eccleston, P. E. (Manager)
IT Services
Facility/equipment: Facility

Cite this

@article{8a9b6b3d8f1240799048a90813733d86,

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

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 {\textquoteleft}hotspot{\textquoteright}, confirm the suitability of zebrafish to study these disease-causing mutations.",

author = "Marston Bradshaw and Squire, {John M} and Edward Morris and Atkinson, {Georgia G} and Rebecca Richardson and Lees, {Jon G} and Massimo Caputo and Bigotti, {Maria Giulia} and Paul, {Danielle M}",

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{\textquoteright}s national Electron Bio-imaging Centre (eBIC) [under proposal EM 32707], funded by the Wellcome Trust, MRC and BBSRC. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = sep,

day = "1",

doi = "10.1007/s10974-023-09653-5",

language = "English",

volume = "44",

pages = "179--192",

journal = "Journal of Muscle Research and Cell Motility",

issn = "0142-4319",

publisher = "Springer Verlag",

number = "3",

}

TY - JOUR

T1 - Zebrafish as a model for cardiac disease; Cryo-EM structure of native cardiac thin filaments from Danio Rerio

AU - Bradshaw, Marston

AU - Squire, John M

AU - Morris, Edward

AU - Atkinson, Georgia G

AU - Richardson, Rebecca

AU - Lees, Jon G

AU - Caputo, Massimo

AU - Bigotti, Maria Giulia

AU - Paul, Danielle M

N1 - 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).

PY - 2023/9/1

Y1 - 2023/9/1

N2 - 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.

AB - 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.

U2 - 10.1007/s10974-023-09653-5

DO - 10.1007/s10974-023-09653-5

M3 - Article (Academic Journal)

C2 - 37480427

SN - 0142-4319

VL - 44

SP - 179

EP - 192

JO - Journal of Muscle Research and Cell Motility

JF - Journal of Muscle Research and Cell Motility

IS - 3

ER -

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

Abstract

Bibliographical note

Access to Document

Handle.net

Fingerprint

Equipment

HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities

Research Data Storage Facility (RDSF)

Cite this