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Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1337-42. doi: 10.1073/pnas.1015125108. Epub 2011 Jan 7.

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

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  • 1Division of Signaling Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 1L7.

Abstract

Stromal interaction molecules (STIM)s function as endoplasmic reticulum calcium (Ca(2+)) sensors that differentially regulate plasma membrane Ca(2+) release activated Ca(2+) 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 Ca(2+)-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 Ca(2+)- and SAM-dependent stabilization of the EF-SAM fold contributes to the disparate regulation of store-operated Ca(2+) entry by STIM1 and STIM2.

PMID:
21217057
[PubMed - indexed for MEDLINE]
PMCID:
PMC3029719
Free PMC Article

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