Functional role of PGAM5 multimeric assemblies and their polymerization into filaments

Karen Ruiz, Tarjani M. Thaker, Christopher Agnew, Lakshmi Miller-Vedam, Raphael Trenker, Clara Herrera, Maria Ingaramo, Daniel Toso, Adam Frost and Natalia Jura ()
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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
Natalia Jura: University of California San Francisco

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08393-w

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