Polymerization of atypical mitochondrial phosphatase PGAM5 underlies its role in cell death and mitochondrial homeostasis

Identification: Ruiz, Karen


Polymerization of atypical mitochondrial phosphatase PGAM5 underlies its role in cell death and mitochondrial homeostasis
Karen Ruiz1, Tarjani Thaker1, Christopher Agnew1, Lakshmi Miller-Vedam2, Adam Frost2, Natalia Jura1
1Cardiovascular Research Institute, University of California San Francisco 2Department of Biochemistry and Biophysics, University of California, San Francisco
Phosphoglycerate mutase family member 5 (PGAM5) is an atypical protein phosphatase localized to the mitochondrial membrane through a transmembrane domain tether. PGAM5 is involved in regulation of mitochondrial fission, and has been shown to promote cell death in response to oxidative stress or mitochondrial damage. The cell death response is linked to the cleavage of PGAM5 from mitochondrial membranes, and relocation of PGAM5 to the cytosol. The physiological importance of PGAM5 is underscored by genetic studies in mice, which revealed that PGAM5 deficiency causes a Parkinson's Disease-like disorder. The mechanism for regulation of the PGAM5 phosphatase domain activity has been poorly understood, and as a result the tools for understanding the biological functions of PGAM5 or manipulation of its activity in disease do not exist. Recent analysis of crystal structures has identified a dodecameric ring assembly of PGAM5 phosphatase domains in complex with its multimerization domain, which has previously been shown to be necessary for full phosphatase activity. Using electron cryo-microscopy we demonstrate that PGAM5 adopts the dodecameric structure in solution and we show for the first time that this assembly is critical for PGAM5 phosphatase activity and its role in mitochondrial homeostasis. Furthermore, our electron microscopy analysis of the purified PGAM5 reveals that the cleaved form of PGAM5 organizes into long filaments composed of the dodecameric PGAM5 rings. Using super resolution microscopy, we demonstrate the presence of these filaments in the cytoplasm of intact cells. Our results suggest PGAM5 oligomerization is linked to the function of PGAM5 as an activator of cell death. Together, this work sheds insights into phosphatase regulation relying on higher-order oligomerization into prion-like filaments and provides an opportunity to further understand the role of phosphatase function in the propagation of cell death.


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