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UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome

Author

Listed:
  • Antonia Vogel

    (Vienna BioCenter)

  • Renato Arnese

    (Vienna BioCenter)

  • Ricardo M. Gudino Carrillo

    (Vienna BioCenter
    Medical University)

  • Daria Sehr

    (Vienna BioCenter)

  • Luiza Deszcz

    (Vienna BioCenter)

  • Andrzej Bylicki

    (Vienna BioCenter)

  • Anton Meinhart

    (Vienna BioCenter)

  • Tim Clausen

    (Vienna BioCenter
    Vienna BioCenter Core Facilities)

Abstract

Myosin motors are critical for diverse motility functions, ranging from cytokinesis and endocytosis to muscle contraction. The UNC-45 chaperone controls myosin function mediating the folding, assembly, and degradation of the muscle protein. Here, we analyze the molecular mechanism of UNC-45 as a hub in myosin quality control. We show that UNC-45 forms discrete complexes with folded and unfolded myosin, forwarding them to downstream chaperones and E3 ligases. Structural analysis of a minimal chaperone:substrate complex reveals that UNC-45 binds to a conserved FX3HY motif in the myosin motor domain. Disrupting the observed interface by mutagenesis prevents myosin maturation leading to protein aggregation in vivo. We also show that a mutation in the FX3HY motif linked to the Freeman Sheldon Syndrome impairs UNC-45 assisted folding, reducing the level of functional myosin. These findings demonstrate that a faulty myosin quality control is a critical yet unexplored cause of human myopathies.

Suggested Citation

  • Antonia Vogel & Renato Arnese & Ricardo M. Gudino Carrillo & Daria Sehr & Luiza Deszcz & Andrzej Bylicki & Anton Meinhart & Tim Clausen, 2024. "UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50442-6
    DOI: 10.1038/s41467-024-50442-6
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    References listed on IDEAS

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    1. Netta Shemesh & Juman Jubran & Shiran Dror & Eyal Simonovsky & Omer Basha & Chanan Argov & Idan Hekselman & Mehtap Abu-Qarn & Ekaterina Vinogradov & Omry Mauer & Tatiana Tiago & Serena Carra & Anat Be, 2021. "The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Doris Hellerschmied & Anita Lehner & Nina Franicevic & Renato Arnese & Chloe Johnson & Antonia Vogel & Anton Meinhart & Robert Kurzbauer & Luiza Deszcz & Linn Gazda & Michael Geeves & Tim Clausen, 2019. "Molecular features of the UNC-45 chaperone critical for binding and folding muscle myosin," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    3. Zhiqiang Hou & Pawel M. Wydorski & Valerie A. Perez & Aydé Mendoza-Oliva & Bryan D. Ryder & Hilda Mirbaha & Omar Kashmer & Lukasz A. Joachimiak, 2021. "DnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    5. Arjun S. Adhikari & Darshan V. Trivedi & Saswata S. Sarkar & Dan Song & Kristina B. Kooiker & Daniel Bernstein & James A. Spudich & Kathleen M. Ruppel, 2019. "β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    6. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    7. Doris Hellerschmied & Max Roessler & Anita Lehner & Linn Gazda & Karel Stejskal & Richard Imre & Karl Mechtler & Alexander Dammermann & Tim Clausen, 2018. "UFD-2 is an adaptor-assisted E3 ligase targeting unfolded proteins," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    8. Melanie Meister-Broekema & Rebecca Freilich & Chandhuru Jagadeesan & Jennifer N. Rauch & Rocio Bengoechea & William W. Motley & E. F. Elsiena Kuiper & Melania Minoia & Gabriel V. Furtado & Maria A. W., 2018. "Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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