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Deconstructing sarcomeric structure–function relations in titin-BioID knock-in mice

Author

Listed:
  • Franziska Rudolph

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Claudia Fink

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Judith Hüttemeister

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Marieluise Kirchner

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Michael H. Radke

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    DZHK (German Center for Cardiovascular Research))

  • Jacobo Lopez Carballo

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Eva Wagner

    (University Medical Center Göttingen
    University Medical Center Göttingen
    DZHK (German Center for Cardiovascular Research))

  • Tobias Kohl

    (University Medical Center Göttingen
    University Medical Center Göttingen
    DZHK (German Center for Cardiovascular Research))

  • Stephan E. Lehnart

    (University Medical Center Göttingen
    University Medical Center Göttingen
    DZHK (German Center for Cardiovascular Research))

  • Philipp Mertins

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    Berlin Institute of Health (BIH))

  • Michael Gotthardt

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    DZHK (German Center for Cardiovascular Research)
    Charité Universitätsmedizin, Berlin)

Abstract

Proximity proteomics has greatly advanced the analysis of native protein complexes and subcellular structures in culture, but has not been amenable to study development and disease in vivo. Here, we have generated a knock-in mouse with the biotin ligase (BioID) inserted at titin’s Z-disc region to identify protein networks that connect the sarcomere to signal transduction and metabolism. Our census of the sarcomeric proteome from neonatal to adult heart and quadriceps reveals how perinatal signaling, protein homeostasis and the shift to adult energy metabolism shape the properties of striated muscle cells. Mapping biotinylation sites to sarcomere structures refines our understanding of myofilament dynamics and supports the hypothesis that myosin filaments penetrate Z-discs to dampen contraction. Extending this proof of concept study to BioID fusion proteins generated with Crispr/CAS9 in animal models recapitulating human pathology will facilitate the future analysis of molecular machines and signaling hubs in physiological, pharmacological, and disease context.

Suggested Citation

  • Franziska Rudolph & Claudia Fink & Judith Hüttemeister & Marieluise Kirchner & Michael H. Radke & Jacobo Lopez Carballo & Eva Wagner & Tobias Kohl & Stephan E. Lehnart & Philipp Mertins & Michael Gott, 2020. "Deconstructing sarcomeric structure–function relations in titin-BioID knock-in mice," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16929-8
    DOI: 10.1038/s41467-020-16929-8
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    Cited by:

    1. Dingxi Zhou & Mariana Borsa & Daniel J. Puleston & Susanne Zellner & Jesusa Capera & Sharon Sanderson & Martina Schifferer & Svenja S. Hester & Xin Ge & Roman Fischer & Luke Jostins & Christian Behren, 2022. "Mapping autophagosome contents identifies interleukin-7 receptor-α as a key cargo modulating CD4+ T cell proliferation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Elena Ortiz-Zapater & Dustin C. Bagley & Virginia Llopis Hernandez & Luke B. Roberts & Thomas J. A. Maguire & Felizia Voss & Philipp Mertins & Marieluise Kirchner & Isabel Peset-Martin & Grzegorz Wosz, 2022. "Epithelial coxsackievirus adenovirus receptor promotes house dust mite-induced lung inflammation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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