Biological & Soft Matter Seminar: From Membrane Fusion to Isoprenoid Biosynthesis: Atomic-Resolution Insights into Protein Function

Abstract:

Understanding how protein structure gives rise to biological function is essential for elucidating disease mechanisms and developing new therapeutic strategies. Our laboratory combines structural biology, biophysics, biochemistry, and computational approaches to uncover the molecular mechanisms that govern proteins involved in human physiology and disease. In this seminar, I will present two examples illustrating how integrative structural biology provides mechanistic insight into complex biological systems. First, I will discuss our work on the human cis-prenyltransferase complex, the enzyme responsible for synthesizing dolichols, essential lipid carriers required for protein N-glycosylation. Using X-ray crystallography, along with complementary biochemical and biophysical approaches, we uncovered the structural organization of the enzyme, elucidated the molecular basis of disease-associated mutations, and revealed a dynamic mechanism that enables the synthesis of long-chain isoprenoids despite the apparent spatial constraints of the active site. In the second part, I will focus on chloride intracellular channel (CLIC) proteins, an unusual family of metamorphic proteins whose physiological function has remained controversial for decades. I will describe our recent findings suggesting that CLIC proteins undergo environmentally driven conformational transitions that promote membrane interaction and fusion, providing a new framework for understanding their cellular roles. Together, these studies demonstrate how integrating multiple structural and functional approaches can bridge atomic-resolution structures with biological mechanisms, revealing fundamental principles of protein function while providing new insights into human disease.