Michael Overduin
Department of Biochemistry, Faculty of Medicine & Dentistry, University of Alberta
Structural biology of signaling and membrane trafficking using NMR, MODA and SMALP tools
Host: Eurico Cabrita
Abstract:
The overall aim of the Overduin lab is to determine how proteins recognize and organize lipids in biological membranes. We are elucidating the mechanism of an E. coli protein called YraP, 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. Our approach is to use NMR to solve peripheral membrane protein structures, measure their interactions with single lipid molecules and micelles, and then validate the lipid ligands and binding determinants in cell-based assays. Our past successes include the discovery of the phosphatidylinositide ligands of FYVE, FAPP-PH, P4M and PX domains which mediate selective localization to specific subcellular membranes. Software tools are also being developed to discover novel protein:lipid interactions, including a computational tool (MODA) that rapidly and accurately predicts membrane optimal docking areas on any protein structure. The group has also led in the discovery of polymer-based nanodiscs for native lipid-protein complex solubilization. Finally, drug-like ligands for therapeutic targets including kinases 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.
Short Bio:
Michael Overduin has been a Professor and CAIP Chair in the Department of Biochemistry at the University of Alberta since 2015, where he serves as Director of NANUC, Canada’s national NMR centre in Edmonton. He was the 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 the development of mechanistic understanding of progression of cancer, infection and prion diseases. He focuses on mechanisms of 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 the RhoA-Lbc complex. Methods including NMR are being used and developed 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).