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Structural basis of substrate recognition and allosteric activation of the proapoptotic mitochondrial HtrA2 protease

Author

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  • Emelie E. Aspholm

    (University of Gothenburg
    University of Gothenburg)

  • Jens Lidman

    (University of Gothenburg
    University of Gothenburg)

  • Björn M. Burmann

    (University of Gothenburg
    University of Gothenburg)

Abstract

The mitochondrial serine protease HtrA2 is a human homolog of the Escherichia coli Deg-proteins exhibiting chaperone and proteolytic roles. HtrA2 is involved in both apoptotic regulation via its ability to degrade inhibitor-of-apoptosis proteins (IAPs), as well as in cellular maintenance as part of the cellular protein quality control machinery, by preventing the possible toxic accumulation of aggregated proteins. In this study, we use advanced solution NMR spectroscopy methods combined with biophysical characterization and biochemical assays to elucidate the crucial role of the substrate recognizing PDZ domain. This domain regulates the protease activity of HtrA2 by triggering an intricate allosteric network involving the regulatory loops of the protease domain. We further show that divalent metal ions can both positively and negatively modulate the activity of HtrA2, leading to a refined model of HtrA2 regulation within the apoptotic pathway.

Suggested Citation

  • Emelie E. Aspholm & Jens Lidman & Björn M. Burmann, 2024. "Structural basis of substrate recognition and allosteric activation of the proapoptotic mitochondrial HtrA2 protease," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48997-5
    DOI: 10.1038/s41467-024-48997-5
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    1. Julie M. Jones & Pinaki Datta & Srinivasa M. Srinivasula & Weizhen Ji & Sanjeev Gupta & ZhiJia Zhang & Erika Davies & György Hajnóczky & Thomas L. Saunders & Margaret L. Van Keuren & Teresa Fernandes-, 2003. "Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice," Nature, Nature, vol. 425(6959), pages 721-727, October.
    2. F. Ulrich Hartl & Andreas Bracher & Manajit Hayer-Hartl, 2011. "Molecular chaperones in protein folding and proteostasis," Nature, Nature, vol. 475(7356), pages 324-332, July.
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