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

作者：Zheng Le; Stathopulos Peter B; Schindl Rainer; Li Guang Yao; Romanin Christoph; Ikura Mitsuhiko^*

来源：Proceedings of the National Academy of Sciences, 2011, 108(4): 1337-1342.

DOI：10.1073/pnas.1015125108

• NMR structure
• protein stability
• STIM2
• store-operated calcium entry

Stromal interaction molecules (STIM)s function as endoplasmic reticulum calcium (Ca(2+)) sensors that differentially regulate plasma membrane C 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 a 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.

• 出版日期2011-1-25