QB3 Postdoc Seminar
Seminar | January 13 | 4:30-5:30 p.m. | 106 Stanley Hall
Speaker 1: Goran Stjepanovic (Jim Hurley lab)
Role of the human Vps15 kinase in PI3K complex I mediated autophagy regulation
Autophagy is basic catabolic pathway for the controlled degradation of cellular components. The class III phosphatidylinositol 3‐kinase complex (PI3KC3) phosphorylates phosphatidylinositol to generate phosphatidylinositol 3‐phosphate, which is essential to initiate autophagy. We have previously reported the structural architecture of the complex and suggested a mechanism for the regulation of the lipid kinase activity by the regulatory signals. However, a long standing question about role of serine/threonine protein kinase Vps15 in the PI3KC3 complex remained unanswered. In this study we demonstrate that catalytic Vps15 mutations prevent delivery of cargo proteins to the vacuole and lead to inhibition of autophagy in yeast. Our hybrid structural biology approach describes the molecular mechanism of Vps15 mediated assembly of the PI3KC3 complex. We show the full range of PI3KC3 domain movements that occur in solution and determinate the critical role of conformation flexibility in PI3K complex activity. Our findings reveal the major mechanism of regulation of PI3K lipid kinase activity required in early stages of autophagosome formation.
Speaker 2: Chun Yang (David Schaffer lab)
Understanding the Functional Role of Eph Receptor Clustering in Neurogenesis
Cellular signal transduction often initiates with the multivalent interactions of ligands, either secreted or cell surface bound, to target cell receptors, leading to receptor clustering. Multivalent binding between ephrin and Eph receptors, which induces Eph clustering, has been found to play major roles in neurogenesis, immunology as well as the progression of cancer. However, current knowledge of the functional relationships between receptor clustering and signal activation, including how the latter depends on the number and spatial organization of receptors in a cluster, is limited. It was recently discovered that the interaction between EphB4 and eprhin-B2 regulates the neuronal differentiation of adult neural stem cells in the brain. Using this model system, we engineered a series of novel multivalent EphB4 binding ligands to control the number, size, and nanoscale spatial organization of EphB4 receptors in a cluster. With this synthetic tool, we investigated relationships between cluster properties, downstream signaling, and ultimately cell differentiation of neural stem cells. This work will have important implications for Eph signaling in many systems including neuroscience, immunology, and cancer biology as well as other receptor-ligand systems where oligomerization is critical for signaling.
Refreshments will be served at 4:15 pm in the lobby.