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| | Figure 1. Amino acid sequence of the human s100A1 monomer. Residues involved in binding Ca2+ are shown with downward arrows. Elements of secondary structure are indicated. |
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| Description | S100A1 is a member of the S100 family of Ca2+-binding proteins. S100A1 exists as a dimer of two identical monomers. Each monomer contains 94 amino acids (figure 1), has a molecular weight of 10546 Da, and contains two EF-hand Ca2+-binding domains (Wright et al., 2005). The non-canonical amino terminal EF-hand contains 14 amino acids and is characteristic of S100 proteins. The carboxy terminal canonical EF-hand contains 12 amino acids and is characteristic of all S100/calmodulin/troponin superfamily members. Like other members of this superfamily, S100A1 possesses no inherent enzymatic activity and exerts its biological effects by interacting with and modulating the activity of target proteins (Zimmer et al., 2003). S100A1 undergoes an ~90 degree rotation of helix 3 upon binding calcium (figure 2), exposing a hydrophobic pocket that serves as the binding site for intracellular and extracellular proteins targets (Landar et al., 1998; Wright et al., 2009b; Zimmer and Weber, 2010). The amino acid sequence linking the two EF-hands confers family member-specific binding for some target proteins (Zimmer and Weber, 2010). |
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| | Figure 2. The conformational change of the S100A1 dimer. Upon binding Ca2+, alpha-helix 3 (blue) undergoes an ~90 degree rotation, exposing a hydrophobic binding site that can interact with a variety of biological targets. Here, a peptide derived from ryanodine receptor (RyRPep; red) is shown binding to S100A1 (Wright et al., 2008). |
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| Expression | S100 proteins are expressed exclusively in higher chordates in a cell-type and tissue-specific manner (Zimmer et al., 1995; Zimmer et al., 2005). It is the unique complement of S100 family members expressed in individual cells that allows cells to transduce changes in calcium levels into unique biological responses. While there are species-specific differences in S100A1 levels, all species exhibit intermediate to high levels of S100A1 in heart, skeletal muscle, smooth muscle, skin, brain, adipose and kidney (Kato et al., 1986; Zimmer and Van Eldik, 1987; Zimmer et al., 1991; Zimmer et al., 1995; Zimmer et al., 2005; Song and Zimmer, 1996; Kiewitz et al., 2000). Lung, liver, spleen, intestine, testis, thyroid gland, salivary gland, pancreas, ovary, placenta and prostate also contain detectable levels of S100A1 protein/mRNA. |
| Localisation | In non-muscle cells, S100A1 is located in the perinuclear cytoplasm. In muscle cells, S100A1 co-localizes with the sarcolemma, sarcoplasmic reticulum and mitochondria. Extracellular forms of S100A1 have also been detected (Most et al., 2003; Hernández-Ochoa et al., 2009). |
| Function | Like other S100 proteins, S100A1 has been implicated in a variety of biological and cellular processes. S100A1 mediates the suppression of chondrocyte differentiation (Saito et al., 2007). In the nervous system, S100A1 modulates innate fear and exploration of novel stimuli (Ackermann et al., 2006). In neuronal cells, S100A1 regulates cell proliferation, dendrite formation, intracellular calcium levels, microtubule stability, and amyloid precursor protein levels (Zimmer et al., 1995; Zimmer et al., 2005). In ganglion neurons, exogenous S100A1 increases sympathetic output by enhancing L-type calcium channel currents in a PKA-dependent manner (Hernández-Ochoa et al., 2009). In the heart, S100A1 regulation of the ryanodine receptor, SERCA pump and phospholamban alters Ca2+ handling; regulation of titin alters contractile performance; and regulation F1-ATPase alters mitochondrial energy metabolism (Rohde et al., 2010). In skeletal muscle, S100A1 interaction with the ryanodine receptor modulates excitation contraction coupling (Prosser et al., 2008; Wright et al, 2008). In endothelial cells, S100A1 moldulates calcium levels and nitric oxide production (Pleger et al., 2008). Additional S100A1 target proteins include the RAGE receptor, aldolase, annexin A6, the actin-capping protein CAPZA1, desmin, glial fibrillary acidic protein, the 43 kD gap junction protein (GJA1), heat shock proteins, immunophilins (CyP40 and FKBP52) phosphoglucomutase, glycogen phosphorylase kinase, tubulin, the calcyclin binding protein, and other S100s (S100A3, S100A4, S100B, S100P) (Wright et al, 2009b). Two structures of S100A1-target complexes have been characterized using NMR (Wright et al., 2008; Wright et al., 2009a). |
| Homology | Species comparisons
Human - Chimpanzee: 100%
Human - Cow: 99%
Human - Canine: 98%
Human - Rat: 94%
Human - Mouse: 94% Other S100 family members
Human S100A1 - Human S100A4: 51%
Human S100A1 - Human S100A5: 46%
Human S100A1 - Human S100A7: 24%
Human S100A1 - Human S100A10: 48%
Human S100A1 - Human S100A13: 41%
Human S100A1 - Human S100B: 60%
Human S100A1 - Human S100P: 56% |
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| Landar A, Rustandi RR, Weber DJ, Zimmer DB. |
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| S100A1 binds to the calmodulin-binding site of ryanodine receptor and modulates skeletal muscle excitation-contraction coupling. |
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| S100A1 and S100B, transcriptional targets of SOX trio, inhibit terminal differentiation of chondrocytes. |
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