Interdisciplinary research focused on biological membranes has revealed them as signaling and trafficking platforms for processes fundamental to life. Biomembranes harbor receptors, ion channels, lipid domains, lipid signals, and scaffolding complexes, which function to maintain cellular growth, metabolism, and homeostasis. Moreover, abnormalities in lipid metabolism attributed to genetic changes among other causes are often associated with diseases such as cancer, arthritis and diabetes. Thus, there is a need to comprehensively understand molecular events occurring within and on membranes as a means of grasping disease etiology and identifying viable targets for drug development. A rapidly expanding field in the last decade has centered on understanding membrane recruitment of peripheral proteins. This class of proteins reversibly interacts with specific lipids in a spatial and temporal fashion in crucial biological processes. Typically, recruitment of peripheral proteins to the different cellular sites is mediated by one or more modular lipid-binding domains through specific lipid recognition. Structural, computational, and experimental studies of these lipid-binding domains have demonstrated how they specifically recognize their cognate lipids and achieve subcellular localization. However, the mechanisms by which these modular domains and their host proteins are recruited to and interact with various cell membranes often vary drastically due to differences in lipid affinity, specificity, penetration as well as protein-protein and intramolecular interactions. As there is still a paucity of predictive data for peripheral protein function, these enzymes are often rigorously studied to characterize their lipid-dependent properties. Our research is targeted at identifying peripheral protein drug targets, designing predictive functions for this class of proteins, and understanding their biological mechanisms of activation as a means of creating better therapies. The below points highlight the different avenues of research in the Stahelin lab:

1. Molecular Basis of Viral Assembly. We are investigating how viruses assemble at the plasma membrane of human cells to form the bud site for generation of a new viral particle.  Funded by NIAID.

 

2. Discovery of New Lipid-Binding Domains. Integration of computational biology, bioinformatics, structural biology, biochemistry, biophysics, and cell biology to discover new lipid-binding domains in the human genome.

 

3. Metals in Medicine.  We have discovered a number of prosurvival factors in cancer and heart disease are regulated by copper.  We are investigating how copper regulates both the normal and aberrant function of these enzymes.  Funded by ACS.

 

4. Lipid-Mediated Regulation of Proinflammatory Enzymes. We are elucidating the role of phosphoinositides and sphingolipids in the regulation of proinflammatory enzymes. Funded by the AHA.