Oral Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Emerging roles of multimeric kinase and phosphatase assemblies in signal transduction (#43)

Natalia Jura 1
  1. UCSF, San Francisco, United States

HER3 is a pseudokinase receptor which signals as a co-receptor of EGFR or HER2. HER3 is essential for cellular homeostasis and frequently subject to deregulation in a broad spectrum of human diseases. I will discuss our recent work in which structural studies and super resolution microscopy (STORM) revealed unique and unexpected mechanisms by which HER3 pseudokinase is misregulated by mutations in cancer and primed for signaling through higher-order oligomerization with EGFR and HER2 co-receptors. I will also present our recent findings describing mechanisms for signaling by an atypical phosphatase, PGAM5, which is 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. Our single particle electron microscopy analysis of the purified PGAM5 reveals that 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. We also provide evidence that PGAM5 oligomerization is linked to its function in controlling mitochondrial architecture and induction of cell death. Together, this work outlines new mechanism for PGAM5 signaling that involves higher-order oligomerization into prion-like filaments and provides an opportunity to further understand the role of this phosphatase in the propagation of cell death.