Proteins are involved in virtually every process within biological systems, and the function that a protein assumes depends on its structure. Determining the structure of a protein is of fundamental importance to understanding protein interactions, the role of proteins in diseases and disorders, drug design and more. Cryo-electron microscopy (cryo-EM) was developed as a cutting-edge alternative to X-ray crystallography, and alleviates the need for crystallization. With recent advances in electron detection and image processing, the resolution by cryo-EM is now beginning to rival X-ray crystallography. Our goal is to employ cryo-EM to determine high resolution structures of important membrane protein complexes involved in cellular signaling, including cellular receptors and ion channels. We also combine structural approaches with functional studies to reveal the structure-function relationships of these membrane proteins.
Structural and functional studies of full-length receptor tyrosine kinases/in Research /by Academic Web Pages
Our major research program focuses on the structural and functional studies of receptor tyrosine kinases (RTKs), a family of cell surface receptors that play a key role in regulating normal cellular processes. Defects in RTK activation are causative in many cancers and other diseases and are targeted by many drugs. To date, many crystal structures for individual domains of RTKs are available. However, structural information on full-length RTKs, either in their apo- or ligand-bound multimeric states, has been elusive because these elongated and conformationally dynamic single-pass transmembrane proteins are difficult to crystalize. Thus, the central question of how information is relayed across plasma membrane by these important proteins remains unanswered.
Structural studies of integral membrane proteins involved in cellular signaling/in Research /by Academic Web Pages
Besides RTKs and ion channels, we are also interested in studying other types of integral transmembrane proteins that play critical roles in cellular signaling, such as STING. The cGAS-cGAMP-STING pathway is a universal mechanism for different type of cells to fight microbial infection. As STING is a small membrane protein having a molecular weight of only ~80 kDa, using cryo-EM to solve the structure of this size of membrane protein is a major challenge. Through the collaboration with Xuewu Zhang and James Chen labs, we determined the high resolution structures of full-length STING with and without cGAMP bound, as well as in the higher order oligomeric state, by using the Volta phase plate.
Structural studies of ion channels and transporters/in Research /by Academic Web Pages
Ion channels and transports are integral membrane proteins that mediate the flow of ions across the membrane. Ion channels are activated by electric potential gradient or ligands, and transporters normally undergo large conformational changes to conduct ions. Ryanodine receptors (RYRs), a class of calcium channels that release calcium from cellular organelles, is the first ion channel we worked on, through the collaboration with Nieng Yan lab.