Abstract
Changes in the intracellular calcium concentration govern cytoskeletal rearrangement, mitosis, apoptosis, transcriptional regulation or synaptic transmission, thereby, regulating cellular effector and organ functions. Calcium binding proteins respond to changes in the intracellular calcium concentration with structural changes, triggering enzymatic activation and association with downstream proteins. One type of calcium binding proteins are EF-hand super family proteins. Here, we describe two recently discovered homologous EF-hand containing adaptor proteins, Swiprosin-1/EF-hand domain containing 2 (EFhd2) and Swiprosin-2/EF-hand domain containing 1 (EFhd1), which are related to allograft inflammatory factor-1 (AIF-1). For reasons of simplicity and concision we propose to name Swiprosin-1/EFhd2 and Swiprosin-2/EFhd1 from now on EFhd2 and EFhd1, according to their respective gene symbols. AIF-1 and Swiprosin-1/EFhd2 are already present in Bilateria, for instance in Drosophila melanogaster and Caenhorhabditis elegans. Swiprosin-2/EFhd1 arose later from gene duplication in the tetrapodal lineage. Secondary structure prediction of AIF-1 reveals disordered regions and one functional EF-hand. Swiprosin-1/EFhd2 and Swiprosin-2/EFhd1 exhibit a disordered region at the N-terminus, followed by two EF-hands and a coiled-coil domain. Whereas both proteins are similar in their predicted overall structure they differ in a non-homologous stretch of 60 amino acids just in front of the EF-hands. AIF-1 controls calcium-dependent cytoskeletal rearrangement in innate immune cells by means of its functional EF-hand. We propose that Swiprosin-1/EFhd2 as well is a cytoskeleton associated adaptor protein involved in immune and brain cell function. Pro-inflammatory conditions are likely to modulate expression and function of Swiprosin-1/EFhd2. Swiprosin-2/EFhd1, on the other hand, modulates apoptosis and differentiation of neuronal and muscle precursor cells, probably through an association with mitochondria. We suggest furthermore that Swiprosin-2/EFhd1 is part of a cellular response to oxidative stress, which could explain its pro-survival activity in neuronal, muscle and perhaps some malignant tissues.
Highlights
Calcium ions (Ca2+) regulate enzyme activities, cytoskeletal and transcriptional regulation, mitosis or apoptosis, gene expression, synaptic communication and homeostasis of reactive oxygen species (ROS) [1]
The depletion of intracellular Ca2+ stores and the concomitant rise in the cytosolic Ca2+ concentration induces influx of extracellular Ca2+ across the plasma membrane through store operated calcium entry (SOCE) and calcium release activated calcium (CRAC) channels. Key players in this process are stromal interaction molecules 1 and 2 (STIM1 and 2), which sense the depletion of endoplasmic reticulum (ER) Ca2+ stores, and ORAI1, which represents a pore subunit of the CRAC channel
We provide information about the recently described EF-hand proteins Swiprosin-1/EF-hand domain containing 2 (EFhd2) and Swiprosin2/EF-hand domain containing 1 (EFhd1), which are related to another EF-hand protein, allograft inflammatory factor-1 (AIF-1; : ionized calcium-binding adapter molecule 1 (Iba1), ionized calcium binding adapter molecule 1)
Summary
Calcium ions (Ca2+) regulate enzyme activities, cytoskeletal and transcriptional regulation, mitosis or apoptosis, gene expression, synaptic communication and homeostasis of reactive oxygen species (ROS) [1]. The homology between aif and efhd genes is restricted to the region encoding the EF-hand domains (representative result for murine EFhd is shown in Additional file 3, Figure S2) This suggests that calcium binding is the most prominent feature of this protein family. In macrophages and a mast cell line, perhaps in primary mast cells (where EFhd is expressed; our unpublished data), EFhd appears to reveal proinflammatory activities, perhaps through positive regulation of the protein kinase C b/nuclear factor B (PKCb/ NF-B) signaling pathway [29]. Function of EFhd in normal and malignant tissue Using an SDS-gel shift assay EFhd has been shown to bind calcium [88] It associates with the mitochondrial inner membrane [16] and over-expression results in neurite extension of 2Y-3t cells. Targeting of the efhd promoter by Suz should lead to decreased or no expression of EFhd
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