1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics

A novel N-terminal extension in mitochondrial TRAP1 serves as a thermal regulator of chaperone activity

  1. James R Partridge
  2. Laura A Lavery
  3. Daniel Elnatan
  4. Nariman Naber
  5. Roger Cooke
  6. David A Agard  Is a corresponding author
  1. Global Blood Therapeutics, United States
  2. Baylor College of Medicine, United States
  3. Howard Hughes Medical Institute, University of California, San Francisco, United States
  4. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.03487
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  1. James R Partridge
  2. Laura A Lavery
  3. Daniel Elnatan
  4. Nariman Naber
  5. Roger Cooke
  6. David A Agard
(2014)
A novel N-terminal extension in mitochondrial TRAP1 serves as a thermal regulator of chaperone activity
eLife 3:e03487.
https://doi.org/10.7554/eLife.03487
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Abstract

Hsp90 is a conserved chaperone that facilitates protein homeostasis. Our crystal structure of the mitochondrial Hsp90, TRAP1, revealed an extension of the N-terminal β-strand previously shown to cross between protomers in the closed state. Here we address the regulatory function of this extension or 'strap' and demonstrate it's responsibility for an unusual temperature dependence in ATPase rates. This dependence is a consequence of a thermally-sensitive kinetic barrier between the apo 'open' and ATP-bound 'closed' conformations. The strap stabilizes the closed state through trans-protomer interactions. Displacement of cis-protomer contacts from the apo state is rate-limiting for closure and ATP hydrolysis. Strap release is coupled to rotation of the N-terminal domain and dynamics of the nucleotide binding pocket lid. The strap is conserved in higher eukaryotes but absent from yeast and prokaryotes suggesting its role as a thermal and kinetic regulator, adapting Hsp90s to the demands of unique cellular and organismal environments.

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Author details

  1. James R Partridge

    Global Blood Therapeutics, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Laura A Lavery

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Daniel Elnatan

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Nariman Naber

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Roger Cooke

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. David A Agard

    Department of Chemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    agard@msg.ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2014, Partridge et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. James R Partridge
  2. Laura A Lavery
  3. Daniel Elnatan
  4. Nariman Naber
  5. Roger Cooke
  6. David A Agard
(2014)
A novel N-terminal extension in mitochondrial TRAP1 serves as a thermal regulator of chaperone activity
eLife 3:e03487.
https://doi.org/10.7554/eLife.03487

Share this article

https://doi.org/10.7554/eLife.03487

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