The Molecular Basis for SOCE Regulation by SARAF

Since the initial discovery of main SOCE participants, STIM and Orai, numerous other proteins were identified as SOCE modulators. Among them is a transmembrane ER-resident protein SARAF that is proved to inhibit SOCE in a calcium-dependent manner despite the lack of an apparent calcium-binding domain. Upon ER refilling with calcium, SARAF promotes dissociation of the STIM-Orai complex and cessation of calcium entry. The structure of SARAF luminal domain solved with 1.9Å resolution pointed to several unique structural properties likely underlying the SARAF inhibitory effect on SOCE,including a labile disulfide bond and the existence of SARAF in monomer or dimer forms. We will present our efforts in exploring these directions and SARAF calcium dependence and activity regulation with biochemical, electrophysiological and imaging tools.