讲座时间：13:30 — 14:30
题目：Gating mechanisms of the CFTR and TRPM2 ion channels
The Howard Hughes Medical Institute and the Rockefeller University
Cystic fibrosis (CF) is the most common lethal genetic disorder in populations of Northern European descent, affecting one out of every 2,500 newborns. It is caused by mutations in a single gene, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR belongs to the ATP-binding cassette (ABC) transporter superfamily, but it is unique among ABC proteins in that it functions as an anion channel. We solved the cryo-EM structures of CFTR in two functional states: the dephosphorylated, ATP-free (closed) and the phosphorylated, ATP-bound (flicker-closed) conformations. By correlating with a mass of functional studies people have done, we get strong insights into the understanding of how CFTR evolves from transporter to channel as well as its gating mechanism.
Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel required for immune cell activation, insulin secretion, and body heat control. TRPM2 is activated by cytosolic Ca2+, phosphatidyl-inositol-4,5-bisphosphate (PIP2) and ADP ribose. We determined the ~3 Å resolution cryo-EM structure of TRPM2 from Nematostella vectensis (63% similar in sequence to human TRPM2) in the Ca2+-bound closed state. Compared to other TRPM channels, TRPM2 exhibits unique structural features that correlate with its function. Together with the electrophysiology studies, we provide a molecular understanding of the unique gating mechanism of TRPM2.