Calendario de eventos
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 include 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.