The inactivation domain of STIM1 acts through intramolecular binding to the coiled-coil domain in the resting state

Abstract

Store-operated calcium entry (SOCE) is a major Ca2+ influx pathway that is controlled by the ER Ca2+ sensor STIM1. Abnormal activation of STIM1 directly influences Ca2+ influx, resulting in severe diseases such as Stormorken syndrome. The inactivation domain of STIM1 (IDstim) has been identified as essential for Ca2+ dependent inactivation of STIM1 (CDI) after SOCE occurs. However, it is unknown whether IDstim is involved in keeping STIM1 inactive before CDI. Herein, we show that IDstim helps STIM1 keep inactive through intramolecular binding with the coiled-coil domain. Between IDstim and the coiled-coil domain, we found a short conserved linker whose extension or mutation constitutively activates STIM1. We have demonstrated that IDstim needs the coiled-coil domain 1 (CC1) to inhibit the CRAC activation domain (CAD) activity and binds to CC1-CAD fragment. Serial deletion of CC1 revealed CC1α1 as a co-inhibitory domain of IDstim. CC1α1 deletion or leucine substitution, which abolishes the closed conformation, impaired the inhibitory effect and binding of IDstim. These results suggest that IDstim cooperates with CC1α1 to helps STIM1 keep inactive under resting conditions.