Evolutionary origins of STIM1 and STIM2 within ancient Ca2+ signaling systems

Abstract

Human stromal interaction molecule (STIM) proteins are parts of elaborate eukaryotic Ca(2+) signaling systems that include numerous plasma membrane (PM), endoplasmic reticulum (ER), and mitochondrial Ca(2+) transporters, channels and regulators. STIM2 and STIM1 function as Ca(2+) sensors with different sensitivities for ER Ca(2+). They translocate to ER-PM junctions and open PM Orai Ca(2+) influx channels when receptor-mediated Ca(2+) release lowers ER Ca(2+) levels. The resulting increase in cytosolic Ca(2+) leads to the activation of numerous Ca(2+) effector proteins that in turn regulate differentiation, cell contraction, secretion and other cell functions. In this review, we use an evolutionary perspective to survey molecular activation mechanisms in the Ca(2+) signaling system, with a particular focus on regulatory motifs and functions of the two STIM proteins. We discuss the presence and absence of STIM genes in different species, the order of appearance of STIM versus Orai, and the evolutionary addition of new signaling domains to STIM proteins.

Figure 1

Schematic representation of relevant Ca²⁺ regulators. Shown is a diagram of a eukaryotic cell with the localization of PM channels (VGCC, CNGCC, TRP, ORAI), Ca²⁺ pumps (PMCA, SERCA, SPCA), internal channels (IP3R), Ca²⁺ exchangers (NCX, LETM1), and key regulatory proteins (STIM, MICU1) indicated. Also indicated are approximate values for the Ca²⁺ concentration in the extracellular space (~1 mM), the cytoplasm (~50 nM under basal conditions), and the ER (~400 µM).

Figure 2

Phylogenetic profiles of eukaryotic Ca²⁺ signal generating genes. (a) A consensus cladogram showing the topology (branch lengths are not intended to be to scale) of the phylogenetic relationships between the species shown in b^,–. Colored type is used to indicate membership in different major branches of the eukaryotic tree. The dotted line joining the major branches indicates an unclear phylogenetic relationship. (b) A representative set of species with sequenced genomes are labeled on the left. Human gene families are listed below (e.g., “STIM” includes the genes STIM1 and STIM2). Yellow indicates evidence for the presence of a homolog of a human gene family in a particular species, and black indicates the lack of an apparent homolog^{,,–,,,,,,,,,,,,–,,,}. (c) Shown is a portion of a multiple sequence alignment of Orai1 homologs. The organism corresponding to each sequence is indicated to the left. Only one sequence is given for human Orai, because the sequences of Orai1, Orai2, and Orai3 are identical in this region. The E106 residue in human Orai1 is indicated with an asterisk. This residue has been implicated as a key determinant of ion specificity.

Figure 3

Evolution of regulatory motifs in STIM proteins. (a) A diagram of the domain organization of human STIM1. The domains are annotated with residue numbers and brief functional descriptions. (b) High-resolution structure of the EF-SAM domain of STIM1 in Ca²⁺-bound form. (c) Diagrams of the domain organization of STIM homologs in Monosiga brevicollis (Monosiga), Hydra magnipapillata (Hydra), Caenorhabditis elegans (C. elegans), Drosophila melanogaster (Drosophila), Danio rerio (Zebrafish), Xenopus laevis (Xenopus), and Homo sapiens (Human). Diagrams for both STIM1 and STIM2 are shown for the vertebrate organisms. Invertebrates and Monosiga brevicollis have only a single STIM homolog. Also included is a distant STIM-related protein in Thalassiosira pseudonana (Diatom). The tree indicates the topology of the phylogenetic relationships between the included STIM proteins.