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Auto-inhibitory role of the EF-SAM domain of STIM proteins in store-operated calcium entry

Stromal interaction molecules (STIM)s function as endoplasmic reticulum calcium (Ca2+) sensors that differentially regulate plasma membrane Ca2+ release activated Ca2+ channels in various cells. To probe the structural basis for the functional differences between STIM1 and STIM2 we engineered a series of EF-hand and sterile α motif (SAM) domain (EF-SAM) chimeras, demonstrating that the STIM1 Ca2+-binding EF-hand and the STIM2 SAM domain are major contributors to the autoinhibition of oligomerization in each respective isoform. Our nuclear magnetic resonance (NMR) derived STIM2 EF-SAM structure provides a rationale for an augmented stability, which involves a 54° pivot in the EF-hand:SAM domain orientation permissible by an expanded nonpolar cleft, ionic interactions, and an enhanced hydrophobic SAM core, unique to STIM2. Live cells expressing “super-unstable” or “super-stable” STIM1/STIM2 EF-SAM chimeras in the full-length context show a remarkable correlation with the in vitro data. Together, our data suggest that divergent Ca2+- and SAM-dependent stabilization of the EF-SAM fold contributes to the disparate regulation of store-operated Ca2+ entry by STIM1 and STIM2.