Speaker: Xiaowei Hoi, Senior Research Scientist - Memorial Sloan Kettering Cancer Center
Title: Structural studies reveal insights into CRAC channel activation
Abstract: The calcium (Ca2+)-release activated Ca2+ (CRAC) channel governs Ca2+ influx necessary for lymphocyte function and immune responses. Function of the CRAC channel requires two proteins: the plasma membrane Ca2+ channel Orai and the channel activator STIM, localized in the endoplasmic reticulum (ER) membrane. Orai is activated through direct interaction with STIM at the ER-plasma membrane junctions in response to Ca2+ depletion in the ER. Crystal structures of drosophila Orai revealed a hexameric assembly of the channel, unique chemical environment of the ion-conducting pore, and structural flexibility at the periphery of the channel. Using a gain-of-function mutation, an open conformation is captured in crystals and confirmed by cryo-electron microscopy studies. These structures provide insights into conformational transitions Orai might undergo leading to pore opening. The interaction of Orai and STIM is under investigation, which will help the understanding of the molecular mechanism of CRAC channel activation in a physiological setting.