We investigate the structural and functional roles of the transmembrane and membrane-proximal regions of cell surface proteins with special focus on immune receptors and viral fusion proteins. Historically, these regions had occupied a "blind spot" in biology because they are often very hydrophobic, sometimes dynamics, and require lipid bilayer environment to be stable.
We find that NMR spectroscopy can be used effectively to unveil these blind spots. To this end, we have pushed technological envelope to characterize the structure and dynamics of membrane systems in near membrane environment. Some of the achievements include 1) the physical basis of the intra-membrane assembly of activating immune receptors, 2) the mechanistic role of the TCR/CD3 signaling motif in receptor triggering, and 3) the discovery that receptor membrane anchor can mediate receptor clustering to drive signaling.
More recently, in another technically challenging project, we revealed the overall architecture of the membrane-related components of the HIV-1 envelope glycoprotein, and these new structures have provided clues to immunogen design for B-cell based HIV-1 vaccine development.
The above projects are still ongoing and expected to generate much more surprises. Moving forward, we are performing a broader survey of the clustering properties of receptor transmembrane domains and their functional roles. We are also applying biophysical and cell biology tools to investigate the structural and functional roles of receptor pre-ligand association and auto-inhibition, with the goal of identifying conformation-specific receptor targets for antibody-based immunotherapy.