The inhibitory helix controls the intramolecular conformational switching of the C-terminus of STIM1.
Store-operated Ca(2+) entry (SOCE) is a critical Ca(2+) signaling pathway in many cell types. After sensing Ca(2+) store depletion in the endoplasmic reticulum (ER) lumen, STIM1 (STromal Interaction Molecule 1) oligomerizes and then interacts with and activates the Orai1 calcium channel. Our previous research has demonstrated that the inhibitory helix (IH) adjacent to the first coiled-coil region (CC1) of STIM1 may keep the whole C-terminus of STIM1 in an inactive state. However, the specific conformational change of CC1-IH that drives the transition of STIM1 from the resting state to the active state remains elusive. Herein, we report the structural analysis of CC1-IH, which revealed that the entire CC1-IH molecule forms a very long helix. Structural and biochemical analyses indicated that IH, and not the CC1 region, contributes to the oligomerization of STIM1. Small-angle X-ray scattering (SAXS) analysis suggested that the C-terminus of STIM1 including the IH region displays a collapsed conformation, whereas the construct without the IH region has an extended conformation. These two conformations may correspond to the conformational states of the C-terminus of STIM1 before and after activation. Taken together, our results provide direct biochemical evidence that the IH region controls the conformational switching of the C-terminus of STIM1.
State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China ; College of Life Sciences, Nankai University, Tianjin, China.
Boyang
B
Cui
Xue
X
Yang
Siwei
S
Li
Zhijie
Z
Lin
Zheng
Z
Wang
Cheng
C
Dong
Yuequan
Y
Shen
D000595:Amino Acid Sequence; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry*; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D053838:Scattering, Small Angle; D016415:Sequence Alignment; D012996:Solutions; D000071737:Stromal Interaction Molecule 1; D014961:X-Ray Diffraction
D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D012996:Solutions; D000071737:Stromal Interaction Molecule 1