S100A1 (S100 calcium binding protein A1)

2011-03-01   Brian R Cannon , Danna B Zimmer , David J Weber 

University of Maryland, Baltimore, MD, USA (BRC, DJW); Texas A&M University, College Station, TX, USA (DBZ)

Identity

HGNC
LOCATION
1q21.3
LOCUSID
ALIAS
S100,S100-alpha,S100A
FUSION GENES

DNA/RNA

Description

The S100A1 gene structure is highly conserved in mammals and contains three exons separated by two introns (Song and Zimmer, 1996; Zimmer et al., 1996; Kiewitz et al., 2000). The first exon encodes the 5 UTR. The second exon encodes the 5 UTR and amino terminal EF hand Ca2+-binding domain. The third exon encodes the carboxy-terminal canonical EF-hand and the 3 UTR. Cis-acting DNA elements that regulate expression in skeletal muscle, neurons, glia and heart have been identified (Song and Zimmer, 1996; Kiewitz et al., 2000). S100A1 transcription in chondrocytes is regulated by the SOX trio of transcription factors, SOX5, SOX6 and SOX9 (Saito et al., 2007).

Transcription

The S100A1 protein is encoded in a 594 bp mRNA transcript. Protein products have not been verified for the five splice variants reconstructed from low abundance cDNAs (Ensembl and Aceview).

Pseudogene

None.

Proteins

Atlas Image
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.

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).
Atlas Image
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).

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%

Mutations

Note

No disease-associated mutations in the S100A1 gene have been reported.

Implicated in

Entity name
Melanoma
Note
Like other S100 proteins, S100A1 displays altered expression patterns in melanomas. Expression is increased in malignant, relative to benign, melanocytic tumors (Sviatoha et al., 2010) and has been proposed as a possible melanoma biomarker (Nonaka et al., 2008).
Entity name
Renal cell carcinoma
Note
It has also been observed that renal cell carcinoma is accompanied by increased expression of S100A1 (Teratani et al., 2002). As with melanoma, S100A1 has been proposed as a marker to differentiate between renal cell carcinoma subtypes (Keijser et al., 2006; Li et al., 2007; Yusenko et al., 2009).
Entity name
Lung cancer
Note
Genomic changes in the S100A1 gene have been reported in lung cancer (Jiang et al., 2010).
Entity name
Alzheimers disease
Note
There is evidence suggesting that S100A1 could be involved in Alzheimers disease (Zimmer et al., 2005). PC12 cells not expressing S100A1 are more resistant to Abeta25-32-induced cell death. Such cells also display a stabilization of intracellular calcium levels similar to that observed in other systems displaying increased resistance to Abeta-induced cell death. These observations suggest that S100A1 antagonists could hinder the progression of Alzheimers disease.
Entity name
Heart disease
Note
The importance of S100A1 in cardiac function was hypothesized in light of two early observations - that S100A1 levels are diminished in cardiac tissues from patients with end stage heart failure (Remppis et al., 1996), but increase during pulmonary hypertension leading to myocardial hypertrophy (Ehlermann et al., 2000). S100A1 is now known to modulate excitation-contraction coupling through interactions with the ryanodine receptor, competing for the same binding site occupied by calmodulin (Prosser et al., 2008; Wright et al., 2008). Furthermore, over-expression of S100A1 delays myocardial remodeling, improves contractile performance, and increases survival in response to myocardial infarction (Kraus et al., 2009; Rohde et al., 2010). This protein is now the subject of gene-therapy studies for treating chronic heart failure (Pleger et al., 2007).

Bibliography

Pubmed IDLast YearTitleAuthors
170456632006S100A1-deficient male mice exhibit increased exploratory activity and reduced anxiety-related responses.Ackermann GE et al
106575942000Right ventricular upregulation of the Ca(2+) binding protein S100A1 in chronic pulmonary hypertension.Ehlermann P et al
196570602009Augmentation of Cav1 channel current and action potential duration after uptake of S100A1 in sympathetic ganglion neurons.Hernández-Ochoa EO et al
208645122010A panel of sputum-based genomic marker for early detection of lung cancer.Jiang F et al
35147941986S100a0 (alpha alpha) protein: distribution in muscle tissues of various animals and purification from human pectoral muscle.Kato K et al
164245362006Immunophenotypic markers to differentiate between benign and malignant melanocytic lesions.Keijser S et al
111089642000Transcriptional regulation of S100A1 and expression during mouse heart development.Kiewitz R et al
195389702009S100A1 in cardiovascular health and disease: closing the gap between basic science and clinical therapy.Kraus C et al
98608581998S100A1 utilizes different mechanisms for interacting with calcium-dependent and calcium-independent target proteins.Landar A et al
173945012007S100A1: a powerful marker to differentiate chromophobe renal cell carcinoma from renal oncocytoma.Li G et al
129601482003Extracellular S100A1 protein inhibits apoptosis in ventricular cardiomyocytes via activation of the extracellular signal-regulated protein kinase 1/2 (ERK1/2).Most P et al
185473462008Differential expression of S100 protein subtypes in malignant melanoma, and benign and malignant peripheral nerve sheath tumors.Nonaka D et al
182925992008Endothelial S100A1 modulates vascular function via nitric oxide.Pleger ST et al
174706932007Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue.Pleger ST et al
180895602008S100A1 binds to the calmodulin-binding site of ryanodine receptor and modulates skeletal muscle excitation-contraction coupling.Prosser BL et al
88988621996Altered expression of the Ca(2+)-binding protein S100A1 in human cardiomyopathy.Remppis A et al
206450372010S100A1: a multifaceted therapeutic target in cardiovascular disease.Rohde D et al
173961382007S100A1 and S100B, transcriptional targets of SOX trio, inhibit terminal differentiation of chondrocytes.Saito T et al
87931021996Expression of the rat S100A1 gene in neurons, glia, and skeletal muscle.Song W et al
200428902010Immunohistochemical analysis of the S100A1, S100B, CD44 and Bcl-2 antigens and the rate of cell proliferation assessed by Ki-67 antibody in benign and malignant melanocytic tumours.Sviatoha V et al
117343382002Induced transcriptional expression of calcium-binding protein S100A1 and S100A10 genes in human renal cell carcinoma.Teratani T et al
198904752009S100A1: Structure, Function, and Therapeutic Potential.Wright NT et al
186504342008S100A1 and calmodulin compete for the same binding site on ryanodine receptor.Wright NT et al
161690122005The three-dimensional solution structure of Ca(2+)-bound S100A1 as determined by NMR spectroscopy.Wright NT et al
196804752009Gene expression profiling of chromophobe renal cell carcinomas and renal oncocytomas by Affymetrix GeneChip using pooled and individual tumours.Yusenko MV et al
161715562005S100-mediated signal transduction in the nervous system and neurological diseases.Zimmer DB et al
17426021991Isolation of a rat S100 alpha cDNA and distribution of its mRNA in rat tissues.Zimmer DB et al
38263571987Tissue distribution of rat S100 alpha and S100 beta and S100-binding proteins.Zimmer DB et al
208274222010The Calcium-Dependent Interaction of S100B with Its Protein Targets.Zimmer DB et al

Other Information

Locus ID:

NCBI: 6271
MIM: 176940
HGNC: 10486
Ensembl: ENSG00000160678

Variants:

dbSNP: 6271
ClinVar: 6271
TCGA: ENSG00000160678
COSMIC: S100A1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000160678ENST00000292169P23297
ENSG00000160678ENST00000292169A0A0S2Z4H2
ENSG00000160678ENST00000368696Q5T7Y4
ENSG00000160678ENST00000368698Q5T7Y6
ENSG00000160678ENST00000436839Q5T7Y5

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Regulation of TLR by endogenous ligandREACTOMER-HSA-5686938

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
155780882004Cardiac adenoviral S100A1 gene delivery rescues failing myocardium.65
192973172009Modulation of the oligomerization state of p53 by differential binding of proteins of the S100 family to p53 monomers and tetramers.47
119099742002Impaired cardiac contractility response to hemodynamic stress in S100A1-deficient mice.39
161690122005The three-dimensional solution structure of Ca(2+)-bound S100A1 as determined by NMR spectroscopy.39
173961382007S100A1 and S100B, transcriptional targets of SOX trio, inhibit terminal differentiation of chondrocytes.36
195389702009S100A1 in cardiovascular health and disease: closing the gap between basic science and clinical therapy.28
129601482003Extracellular S100A1 protein inhibits apoptosis in ventricular cardiomyocytes via activation of the extracellular signal-regulated protein kinase 1/2 (ERK1/2).27
208645122010A panel of sputum-based genomic marker for early detection of lung cancer.26
156540192005Distinct subcellular location of the Ca2+-binding protein S100A1 differentially modulates Ca2+-cycling in ventricular rat cardiomyocytes.21
181931482008Serum levels of S100B, S100A1B and S100BB are all related to outcome after severe traumatic brain injury.21

Citation

Brian R Cannon ; Danna B Zimmer ; David J Weber

S100A1 (S100 calcium binding protein A1)

Atlas Genet Cytogenet Oncol Haematol. 2011-03-01

Online version: http://atlasgeneticsoncology.org/gene/44149/s100a1