Molecular Dynamics Simulations of Membrane-Bound STIM1 to Investigate Conformational Changes during STIM1 Activation upon Calcium Release.
Calcium is involved in important intracellular processes, such as intracellular signaling from cell membrane receptors to the nucleus. Typically, calcium levels are kept at less than 100 nM in the nucleus and cytosol, but some calcium is stored in the endoplasmic reticulum (ER) lumen for rapid release to activate intracellular calcium-dependent functions. Stromal interacting molecule 1 (STIM1) plays a critical role in early sensing of changes in the ER's calcium level, especially when there is a sudden release of stored calcium from the ER. Inactive STIM1, which has a bound calcium ion, is activated upon ion release. Following activation of STIM1, there is STIM1-assisted initiation of extracellular calcium entry through channels in the cell membrane. This extracellular calcium entering the cell then amplifies intracellular calcium-dependent actions. At the end of the process, ER levels of stored calcium are reestablished. The main focus of this work was to study the conformational changes accompanying homo- or heterodimerization of STIM1. For this purpose, the ER luminal portion of STIM1 (residues 58-236), which includes the sterile alpha motif (SAM) domain plus the calcium-binding EF-hand domains 1 and 2 attached to the STIM1 transmembrane region (TM), was modeled and embedded in a virtual membrane. Next, molecular dynamics simulations were performed to study the conformational changes that take place during STIM1 activation and subsequent protein-protein interactions. Indeed, the simulations revealed exposure of residues in the EF-hand domains, which may be important for dimerization steps. Altogether, understanding conformational changes in STIM1 can help in drug discovery when targeting this key protein in intracellular calcium functions.
Department of Chemistry, University of South Florida , Tampa, Florida 33620, United States.
Sreya
S
Mukherjee
Department of Chemistry, University of South Florida , Tampa, Florida 33620, United States.
Aleksandra
A
Karolak
INSERM ESPRI, ERI29/EA2216 Laboratory of Immunotherapy and B Cell Pathologies, Laboratory of Immunology and Immunotherapy, CHRU Morvan, European University of Brittany , F29609 Brest, France.|Network "Ion channels and cancer-Cancéropole Grand Ouest (IC-CGO)" , F29609 Brest, France.|INSERM U1078, Brest University Medical School , F29609 Brest, France.
Marjolaine
M
Debant
Network "Ion channels and cancer-Cancéropole Grand Ouest (IC-CGO)" , F29609 Brest, France.|INSERM U1078, Brest University Medical School , F29609 Brest, France.
Paul
P
Buscaglia
INSERM ESPRI, ERI29/EA2216 Laboratory of Immunotherapy and B Cell Pathologies, Laboratory of Immunology and Immunotherapy, CHRU Morvan, European University of Brittany , F29609 Brest, France.|Network "Ion channels and cancer-Cancéropole Grand Ouest (IC-CGO)" , F29609 Brest, France.
Yves
Y
Renaudineau
Network "Ion channels and cancer-Cancéropole Grand Ouest (IC-CGO)" , F29609 Brest, France.|INSERM U1078, Brest University Medical School , F29609 Brest, France.
Olivier
O
Mignen
Department of Chemistry, University of South Florida , Tampa, Florida 33620, United States.
Wayne C
WC
Guida
Department of Chemistry, University of South Florida , Tampa, Florida 33620, United States.
Wesley H
0000-0002-5604-3769
WH
Brooks
D002118:Calcium / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism*; D000072417:Protein Domains / Q000187:drug effects; D000071737:Stromal Interaction Molecule 1 / Q000737:chemistry* / Q000378:metabolism*
D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium