期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 4, 页码 1337-1342出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1015125108
关键词
NMR structure; protein stability; STIM2; store-operated calcium entry
资金
- Canadian Institutes of Health Research
- Canadian Foundation for Innovation
- Natural Sciences and Engineering Research Council of Canada
- Ontario Cancer Institute
- Austrian Science Fund [P21118]
- Austrian Science Fund (FWF) [P21118] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [P 22747] Funding Source: researchfish
Stromal interaction molecules (STIM)s function as endoplasmic reticulum calcium (Ca2+) sensors that differentially regulate plasma membrane C 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 a 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.
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