Review on S100A1 (S100 calcium binding protein A1), with data on DNA, on the protein encoded, and where the gene is implicated

Cannon, BR

Weber, DJ

Zimmer, DB

Atlas of Genetics and Cytogenetics in Oncology and Haematology

I-Revues

   
 
 
 
 
 
Gene Section 
Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)   873 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology 
OPEN ACCESS JOURNAL AT INIST-CNRS 
S100A1 (S100 calcium binding protein A1) 
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) 
 
Published in Atlas Database: March 2011 
Online updated version : http://AtlasGeneticsOncology.org/Genes/S100A1ID44149ch1q21.html 
DOI: 10.4267/2042/46035 
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Identity 
Other names: S100; S100-alpha; S100A 
HGNC (Hugo): S100A1 
Location: 1q21.3 
Local order: The S100A1 gene is located at the 
telomeric end of the 16 member S100A gene cluster on 
1q21.3. The S100A1 gene is flanked by the S100A13 
(centromeric) and C1orf77 (telomeric) 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 or 
the five splice variants reconstructed from low 
abundance cDNAs (Ensembl and Aceview). 
Pseudogene 
None. 
Protein 
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). 
 
S100A1 (S100 calcium binding protein A1) Cannon BR, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)   874 
 
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. 
 
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 
S100A1 (S100 calcium binding protein A1) Cannon BR, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10)   875 
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 
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 a  
a possible melanoma biomarker (Nonaka et al., 2008). 
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). 
Lung cancer 
Note 
Genomic changes in the S100A1 gene have been 
reported in lung cancer (Jiang et al., 2010). 
Alzheimer's disease 
Note 
There is evidence suggesting that S100A1 could be 
involved in Alzheimer's 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 Alzheimer's disease. 
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 s te 
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). 
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This article should be referenced as such: 
Cannon BR, Zimmer DB, Weber DJ. S100A1 (S100 calcium 
binding protein A1). Atlas Genet Cytogenet Oncol Haematol. 
2011; 15(10):873-876. 


S100A1 (S100 calcium binding protein A1)

BR Cannon

DB Zimmer

DJ Weber

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S100A1 (S100 calcium binding protein A1)

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