Molecular Evolution and Functional Divergence of the Ca2+ Sensor Protein in Store-operated Ca2+ Entry: Stromal Interaction Molecule

Abstract

Receptor-mediated Ca2+ signaling in many non-excitable cells initially induces Ca2+ release from intracellular Ca2+ stores, followed by Ca2+ influx across the plasma membrane. Recent findings have suggested that stromal interaction molecules (STIMs) function as the Ca2+ sensor to detect changes of Ca2+ content in the intracellular Ca2+ stores. Human STIMs and invertebrate STIM share several functionally important protein domains, but diverge significantly in the C-terminus. To better understand the evolutionary significance of STIM activity, phylogenetic analysis of the STIM protein family was conducted after extensive database searching. Results from phylogeny and sequence analysis revealed early adaptation of the C-terminal divergent domains in Urochordata, before the expansion of STIMs in Vertebrata. STIMs were subsequently subjected to one round of gene duplication as early as in the Euteleostomi lineage in vertebrates, with a second round of fish-specific gene duplication. After duplication, STIM-1 and STIM-2 molecules appeared to have undergone purifying selection indicating strong evolutionary constraints within each group. Furthermore, sequence analysis of the EF-hand Ca2+ binding domain and the SAM domain, together with functional divergence studies, identified critical regions/residues likely underlying functional changes, and provided evidence for the hypothesis that STIM-1 and STIM-2 might have developed distinct functional properties after duplication.