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Functional role of PGAM5 multimeric assemblies and their polymerization into filaments

Author

Listed:
  • Karen Ruiz

    (University of California San Francisco)

  • Tarjani M. Thaker

    (University of California San Francisco)

  • Christopher Agnew

    (University of California San Francisco)

  • Lakshmi Miller-Vedam

    (University of California San Francisco)

  • Raphael Trenker

    (University of California San Francisco)

  • Clara Herrera

    (University of California San Francisco)

  • Maria Ingaramo

    (Calico Life Sciences)

  • Daniel Toso

    (University of California Berkeley)

  • Adam Frost

    (University of California San Francisco
    University of California Berkeley
    Chan Zuckerberg Biohub)

  • Natalia Jura

    (University of California San Francisco
    University of California San Francisco)

Abstract

PGAM5 is a mitochondrial protein phosphatase whose genetic ablation in mice results in mitochondria-related disorders, including neurodegeneration. Functions of PGAM5 include regulation of mitophagy, cell death, metabolism and aging. However, mechanisms regulating PGAM5 activation and signaling are poorly understood. Using electron cryo-microscopy, we show that PGAM5 forms dodecamers in solution. We also present a crystal structure of PGAM5 that reveals the determinants of dodecamer formation. Furthermore, we observe PGAM5 dodecamer assembly into filaments both in vitro and in cells. We find that PGAM5 oligomerization into a dodecamer is not only essential for catalytic activation, but this form also plays a structural role on mitochondrial membranes, which is independent of phosphatase activity. Together, these findings suggest that modulation of the oligomerization of PGAM5 may be a regulatory switch of potential therapeutic interest.

Suggested Citation

  • Karen Ruiz & Tarjani M. Thaker & Christopher Agnew & Lakshmi Miller-Vedam & Raphael Trenker & Clara Herrera & Maria Ingaramo & Daniel Toso & Adam Frost & Natalia Jura, 2019. "Functional role of PGAM5 multimeric assemblies and their polymerization into filaments," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08393-w
    DOI: 10.1038/s41467-019-08393-w
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