Every Piece of the Puzzle Matters: A Novel Zinc-Binding Site in the Luminal Domain of STIM1 Drives Clustering

STIM1 is pivotal in the tightly regulated mechanism controlling calcium homeostasis in the ER. It is activated by calcium dissociation from its EF-hand domain when ER calcium levels decrease, leading to its interaction with the ORAI channel to initiate calcium influx. Despite advancements in understanding the complex STIM1 machinery, including its domain organization and structural rearrangements upon activation, many aspects of this process remain poorly understood. In this study, we focused on a small conserved region situated upstream to the EF-hand, which has been previously shown to be involved in the modulation of STIM1 by ROS. Our findings reveal that this region binds zinc and plays a pivotal role in STIM1 activation by promoting its clustering, a process essential for the activation of calcium influx. These results revealed the functional importance of this domain and added a crucial piece to the puzzle of how calcium and zinc signaling are interconnected.