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Structural basis of a redox-dependent conformational switch that regulates the stress kinase p38α

Author

Listed:
  • Joan Pous

    (The Barcelona Institute of Science and Technology)

  • Blazej Baginski

    (The Barcelona Institute of Science and Technology
    Global Health Medicines R&D, GSK)

  • Pau Martin-Malpartida

    (The Barcelona Institute of Science and Technology)

  • Lorena González

    (The Barcelona Institute of Science and Technology
    Grupo Menarini España)

  • Margherita Scarpa

    (The Barcelona Institute of Science and Technology)

  • Eric Aragon

    (The Barcelona Institute of Science and Technology)

  • Lidia Ruiz

    (The Barcelona Institute of Science and Technology)

  • Rebeca A. Mees

    (The Barcelona Institute of Science and Technology)

  • Javier Iglesias-Fernández

    (Nostrum Biodiscovery)

  • Modesto Orozco

    (The Barcelona Institute of Science and Technology
    Universitat de Barcelona)

  • Angel R. Nebreda

    (The Barcelona Institute of Science and Technology
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Maria J. Macias

    (The Barcelona Institute of Science and Technology
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

Abstract

Many functional aspects of the protein kinase p38α have been illustrated by more than three hundred structures determined in the presence of reducing agents. These structures correspond to free forms and complexes with activators, substrates, and inhibitors. Here we report the conformation of an oxidized state with an intramolecular disulfide bond between Cys119 and Cys162 that is conserved in vertebrates. The structure of the oxidized state does not affect the conformation of the catalytic site, but alters the docking groove by partially unwinding and displacing the short αD helix due to the movement of Cys119 towards Cys162. The transition between oxidized and reduced conformations provides a mechanism for fine-tuning p38α activity as a function of redox conditions, beyond its activation loop phosphorylation. Moreover, the conformational equilibrium between these redox forms reveals an unexplored cleft for p38α inhibitor design that we describe in detail.

Suggested Citation

  • Joan Pous & Blazej Baginski & Pau Martin-Malpartida & Lorena González & Margherita Scarpa & Eric Aragon & Lidia Ruiz & Rebeca A. Mees & Javier Iglesias-Fernández & Modesto Orozco & Angel R. Nebreda & , 2023. "Structural basis of a redox-dependent conformational switch that regulates the stress kinase p38α," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43763-5
    DOI: 10.1038/s41467-023-43763-5
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    References listed on IDEAS

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    1. Zhiduan Su & James G. Burchfield & Pengyi Yang & Sean J. Humphrey & Guang Yang & Deanne Francis & Sabina Yasmin & Sung-Young Shin & Dougall M. Norris & Alison L. Kearney & Miro A. Astore & Jonathan Sc, 2019. "Global redox proteome and phosphoproteome analysis reveals redox switch in Akt," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
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