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Structural and Functional Roles of the Membrane-Related Components of Single-Pass Membrane Proteins


PROJECT SUMMARY My laboratory investigates the structural and functional roles of the transmembrane (TM) and membrane- proximal (MP) regions of immune receptors and viral fusion proteins. The single-pass transmembrane (TM) proteins account for the vast majority of signaling receptors on the cell surface, and due to the lack of structural information, the TM/MP regions are often the missing link in our understanding of how extracellular ligand binding is translated to the activation of intracellular signaling pathways. TM and MP regions of single-pass membrane proteins are extremely difficult to visualize. We have developed an effective NMR/biochemistry technology platform for visualizing these regions and found that they can have surprisingly important biological function other than membrane anchoring. We find that a few receptors in the tumor necrosis factor receptor superfamily (TNFRSF) exhibit a previously unknown phenomenon that their transmembrane domains (TMDs) alone can oligomerize in membrane and drive receptor clustering and activation. In another finding, the TM region of the HIV-1 envelope spike form defined trimeric structure that can strongly influence the antigenicity of the ectodomain of the spike currently being used for vaccine development. The above few examples already suggest the enormous potential of uncovering the membrane regions of type I/II membrane proteins in discovering new biological mechanisms, which is the motivation for the proposed research. In the next five years, we will continue to explore the structure and function of TM regions with three specific goals. (1) We will further examine the mechanism of TMD-mediated receptor clustering and activation for other members of the TNFRSF and test the generality of this new concept in receptor biology. (2) We will explore the function of TMD oligomerization in the signaling mechanism of the ? chain cytokine receptors, for which the membrane regions are completely unknown. (3) We will continue to examine the TM and MP regions of other viral fusion proteins such as that of SIV and coronavirus, for understanding how the membrane-interacting components of the fusion proteins stabilize the prefusion state of the envelope spikes and for revealing unique structural features that may be used for testing mechanistic hypotheses of viral membrane fusion.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.