Heinrich Roder

Biography

Throughout my scientific career I have been fascinated by basic problems in protein science, including the mechanism of protein folding, protein structure-function relationships, and the impact of protein dynamics and intrinsic disorder on protein function. My group approaches these fundamental questions using various biophysical tools, including NMR, fluorescence and other optical techniques, rapid kinetics and protein engineering. Some of our most notable contributions include the development of NMR-based hydrogen exchange labeling methods and improved rapid mixing techniques, which have led to a better understanding of early stages of protein folding. These innovative methodologies, combined with rigorous kinetic modeling and protein engineering, have enabled us to characterize the folding/unfolding mechanisms of numerous proteins in great detail, both in terms of structural and temporal resolution. Our observation that proteins of various sizes and structural types encounter compact, partially structured states during early stages of folding have had a profound impact on the field. Our current research is mainly directed at understanding mechanisms of coupled folding/binding reactions. In parallel, we have made extensive use of biomolecular NMR and fluorescence techniques for exploring structure-dynamics-function relationships of a variety of proteins, including de novo designed proteins, a blood clotting factor, several signaling proteins and the inhibitory natural killer cell receptor KIR3DL1, often in collaboration with colleagues at Fox Chase, U. Penn. or Temple U. In a recently completed NIH-funded project we explored the structure, dynamics and interactions of NHERF, a signaling scaffold comprising a pair of PDZ domains as well as long intrinsically disordered regions. NHERF functions as an adapter at the membrane-cytoskeleton interface of epithelial cells and regulates the activity of numerous membrane proteins. By combining our biophysical approaches with cellular imaging and flow cytometry, we gained detailed insight into the mechanism by which NHERF regulates the signaling activity and trafficking of the epidermal growth factor receptor (EGFR). Current research is aimed at understanding how interactions between multivalent scaffold proteins, such as NHERF or the SH2-domain containing phosphatase SHP2, with the intrinsically disordered cytosolic regions of membrane receptors, such as EGFR and KIR3DL1, can mediate receptor clustering and phase separation on the plasma membrane.