Extending the genetic code to the lipidic code: membrane signaling and disease mechanisms
THIS SEMINAR HAS BEEN CANCELLED
Dr. Michael Overduin
April 3 at 12:20pm in the Fralin Auditorium, 102 Fralin Hall
Hosted by Dr. D. Capelluto
Michael Overduin is a Professor in the Department of Biochemistry at the University of Alberta, where he serves as Director of NANUC, Canada’s national NMR centre in Edmonton. He was previously Professor of Structural Biology and Director of the Henry Wellcome Building for NMR, a UK national facility in Birmingham from 2003. He established his first lab at the University of Colorado in Denver in 1996, initiating the Rocky Mountain Regional NMR Facility there. He postdoc’ed at the University of Toronto and earned a PhD at The Rockefeller University in 1993. His lab focuses on structural biology and the discovery of ligands of proteins involved in cell adhesion, signaling and endocytosis. The aim of his group is to better understand the mechanisms underlying progression of cancer, infection and prion diseases. He focuses on desmosomal attachment to the cytoskeletion, phosphoinositide recognition by signaling proteins, and emerging targets including oncogenic Shp2 phosphatases and calcium/calmodulin dependent ser/thr kinases and GTPase regulation. Methods including NMR are being used to identify unexploited interdomain, lipid binding and allosteric sites, with the end goal of providing new avenues for intervention. Ligand screening including with drug fragments are used in the structure-aided design of novel agents for therapeutic intervention for signaling and membrane-embedded targets. Technological contributions include a computational method (“MODA”) which predicts lipid binding surfaces on protein structure, and the Styrene Maleic Acid Lipid Particle (SMALP) system for detergent-free purification of native membrane proteins into stable, soluble nanoparticles, for which he has formed an international network which shares polymers and protocols (www.SMALP.net).
The overall aim of the Overduin lab is to determine how proteins recognize lipid signals and function within biological membranes. Our approach is to use nuclear magnetic resonance (NMR) spectroscopy to elucidate structures of membrane-associated protein structures, measure their interactions with single membrane mimics, and validate the lipid ligands and binding determinants in cell-based assays. The discoveries of the phosphoinositide ligands of signaling domains including FYVE, pleckstrin homology (PH) and phox homology (PX) domains have defined new principles of organization and regulation in eukaryotic cells. We are now elucidating the structure and mechanism of an E. coli protein called YraP (see Figure), which is found in a range of Gram-negative bacteria. The relatives of YraP includes hemolysins, mechanosensitive channels, the membrane-pore forming protein Secretin, and a variety of eukaryotic proteins. We propose that they share a common function based on lipid recognition, and are elucidating the cellular function, molecular interactions and 3D structures. We are determining how this lipoprotein engages the phospholipids found in the membrane that surrounds Gram negative bacteria. Software tools are also being developed including a computational tool (MODA) that rapidly and accurately predicts membrane optimal docking areas on any protein structure. The lab is designing of polymer-based nanodiscs for the study of native membrane protein assemblies including prions and the PagP palmitoyltransferase. Finally, drug-like ligands for therapeutic targets including the CaMK1D kinase and Shp2 phosphatase are being discovered by NMR-based fragment screening. Hybrid structures being solved by NMR, X-ray crystallography and small angle X-ray scattering are revealing the mechanisms of oncogenic states that drive cancer progression.
This seminar will NOT be livestreamed and recorded.