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Phosphorylation activates the yeast small heat shock protein Hsp26 by weakening domain contacts in the oligomer ensemble

Author

Listed:
  • Moritz Mühlhofer

    (Technische Universität München)

  • Carsten Peters

    (Technische Universität München)

  • Thomas Kriehuber

    (Technische Universität München
    Boehringer Ingelheim)

  • Marina Kreuzeder

    (Technische Universität München
    Ludwig-Maximilians-Universität München)

  • Pamina Kazman

    (Technische Universität München
    Roche Diagnostics)

  • Natalia Rodina

    (Technische Universität München
    Deutsches Forschungszentrum für Gesundheit und Umwelt)

  • Bernd Reif

    (Technische Universität München
    Deutsches Forschungszentrum für Gesundheit und Umwelt)

  • Martin Haslbeck

    (Technische Universität München)

  • Sevil Weinkauf

    (Technische Universität München)

  • Johannes Buchner

    (Technische Universität München)

Abstract

Hsp26 is a small heat shock protein (sHsp) from S. cerevisiae. Its chaperone activity is activated by oligomer dissociation at heat shock temperatures. Hsp26 contains 9 phosphorylation sites in different structural elements. Our analysis of phospho-mimetic mutations shows that phosphorylation activates Hsp26 at permissive temperatures. The cryo-EM structure of the Hsp26 40mer revealed contacts between the conserved core domain of Hsp26 and the so-called thermosensor domain in the N-terminal part of the protein, which are targeted by phosphorylation. Furthermore, several phosphorylation sites in the C-terminal extension, which link subunits within the oligomer, are sensitive to the introduction of negative charges. In all cases, the intrinsic inhibition of chaperone activity is relieved and the N-terminal domain becomes accessible for substrate protein binding. The weakening of domain interactions within and between subunits by phosphorylation to activate the chaperone activity in response to proteotoxic stresses independent of heat stress could be a general regulation principle of sHsps.

Suggested Citation

  • Moritz Mühlhofer & Carsten Peters & Thomas Kriehuber & Marina Kreuzeder & Pamina Kazman & Natalia Rodina & Bernd Reif & Martin Haslbeck & Sevil Weinkauf & Johannes Buchner, 2021. "Phosphorylation activates the yeast small heat shock protein Hsp26 by weakening domain contacts in the oligomer ensemble," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27036-7
    DOI: 10.1038/s41467-021-27036-7
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    References listed on IDEAS

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    1. Sophia Ungelenk & Fatemeh Moayed & Chi-Ting Ho & Tomas Grousl & Annette Scharf & Alireza Mashaghi & Sander Tans & Matthias P. Mayer & Axel Mogk & Bernd Bukau, 2016. "Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding," Nature Communications, Nature, vol. 7(1), pages 1-14, December.
    2. Kyeong Kyu Kim & Rosalind Kim & Sung-Hou Kim, 1998. "Crystal structure of a small heat-shock protein," Nature, Nature, vol. 394(6693), pages 595-599, August.
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