# S100A2

## Overview
S100A2 is a gene that encodes the S100 calcium-binding protein A2, a member of the S100 family of EF-hand calcium-binding proteins. This protein is primarily expressed in epithelial tissues and is involved in various cellular processes, including calcium signaling and response to oxidative stress. S100A2 is characterized by its unique nuclear localization and functions as a tumor suppressor in certain contexts, although it can also act as a tumor promoter depending on the cancer type. The protein forms homodimers and undergoes conformational changes upon binding calcium and zinc ions, which modulate its activity and interactions with other proteins. S100A2's interactions with proteins such as p53 and its involvement in signaling pathways underscore its role in cellular homeostasis and cancer biology (Franz1998Binding; Koch2012The; Deshpande2000Biochemical).

## Structure
The S100A2 protein is a member of the S100 family of EF-hand calcium-binding proteins, characterized by its unique nuclear localization and role as a tumor suppressor. The primary structure of S100A2 includes four cysteine residues (Cys2, Cys21, Cys86, Cys93) that are involved in zinc ion coordination (Koch2007Implications). The secondary structure consists of four α-helices organized into two EF-hand motifs, with the N-terminal EF-hand being S100-specific and the C-terminal EF-hand being a classical EF-hand (Randazzo2001Structural; Koch2008Crystal). 

In its tertiary structure, S100A2 forms a homodimer, with each subunit containing 97 residues. The protein undergoes significant conformational changes upon calcium binding, particularly in the C-terminal EF-hand, where helix III reorients by approximately 90°, exposing a hydrophobic cavity that serves as a target protein interaction site (Koch2012The). 

The quaternary structure involves dimerization, which is common among S100 proteins, and is crucial for its function and interactions (Franz1998Binding). S100A2 also binds zinc ions with high affinity, and zinc binding acts as a negative modulator by decreasing calcium affinity (Koch2012The).

## Function
S100A2 is a calmodulin-like protein primarily expressed in epithelial tissues, where it plays a significant role in cellular responses to oxidative stress and calcium signaling. In healthy human keratinocytes, S100A2 is predominantly localized in the nucleus, suggesting it may bind to nuclear components or require a cytosolic cofactor for nuclear export (Deshpande2000Biochemical). The protein exists as a homodimer and can undergo intermolecular disulfide cross-linking in response to oxidative stress, indicating a protective role against carcinogens (Deshpande2000Biochemical).

S100A2 is involved in the regulation of intracellular calcium levels and signaling pathways, facilitated by its EF-hand Ca2+-binding motif (Gonzalez2020Role). It binds four Ca2+ ions per dimer with positive cooperativity, and similar binding is observed for Zn2+, which induces conformational changes important for its regulatory role in the nucleus (Franz1998Binding). The protein's expression is positively regulated by p53 and ErbB signaling pathways, linking it to keratinocyte differentiation and carcinogenesis (Deshpande2000Biochemical).

S100A2's nuclear localization and its ability to form dimers and higher polymers suggest it may link nuclear Ca2+ signals to transcriptional components, potentially acting as a tumor suppressor by influencing gene expression (Franz1998Binding).

## Clinical Significance
The S100A2 gene, part of the S100 family of calcium-binding proteins, plays a complex role in cancer, acting as both a tumor suppressor and promoter depending on the context. In non-small cell lung cancer (NSCLC), S100A2 is often overexpressed, which is associated with increased metastasis and poor prognosis, particularly in early-stage cases. This overexpression is linked to the induction of epithelial-mesenchymal transition (EMT) and activation of the PI3/Akt signaling pathway, enhancing tumor cell survival and invasion (Wolf2010S100A2; Naz2013Protumorigenic). 

In gastric cancer, S100A2 expression is generally reduced, correlating with larger tumor size, deeper invasion, and poorer survival outcomes, making it an independent predictor of survival (ZHAO2013Clinical). Conversely, in esophageal squamous cell carcinoma (ESCC), S100A2 expression is downregulated in early stages but increases in advanced stages, where it is associated with a higher 5-year survival rate (Wolf2010S100A2).

In pancreatic cancer, S100A2 is overexpressed and linked to poor prognosis and advanced disease stages (Li2021Prognostic). The gene's expression is also implicated in colorectal cancer, where high cytoplasmic levels are associated with better cancer-specific survival (Hatthakarnkul2023Protein). These findings highlight the clinical significance of S100A2 expression alterations in cancer prognosis and metastasis.

## Interactions
S100A2 interacts with several proteins in a calcium-dependent manner, playing a role in various cellular processes. It binds to recombinant tropomyosins, suggesting involvement in cytoskeleton organization (Wolf2010S100A2). S100A2 also interacts with the tumor suppressor p53, specifically binding to the tetramerization domain (TET) and the C-terminal negative regulatory domain (NRD) of p53. This interaction affects p53's transcriptional activity and is influenced by p53's phosphorylation and acetylation states (Wolf2010S100A2; SantamariaKisiel2006Calciumdependent). S100A2 can bind to monomeric, dimeric, and tetrameric forms of p63 and p73, showing higher affinity for their TET domains than for p53 (Wolf2010S100A2).

S100A2 also interacts with the tetratricopeptide repeat (TPR) domains of hsp70/hsp90-organizing protein (Hop) and kinesin-light chain (KLC) (Wolf2010S100A2). It binds to FKBP38, inhibiting its interaction with Bcl-2 and Hsp90, which suggests a regulatory mechanism in FKBP38-mediated signaling pathways (Hountis2014S100A2). Additionally, S100A2, along with S100P, binds to the TPR domain of the U-box E3 ubiquitin ligase CHIP, interfering with CHIP's interactions with Hsp70, Hsp90, HSF1, and Smad1, and affecting the ubiquitination and degradation of mutant p53 (Hountis2014S100A2). S100A2 also interacts with the receptor for advanced glycation endproducts (RAGE), particularly with its V-domain, impacting the motility of certain cancer cell lines (Wolf2010S100A2).


## References


[1. (Randazzo2001Structural) Antonio Randazzo, Christian Acklin, Beat W. Schäfer, Claus W. Heizmann, and Walter J. Chazin. Structural insight into human zn2+-bound s100a2 from nmr and homology modeling. Biochemical and Biophysical Research Communications, 288(2):462–467, October 2001. URL: http://dx.doi.org/10.1006/BBRC.2001.5793, doi:10.1006/bbrc.2001.5793. This article has 30 citations and is from a peer-reviewed journal.](https://doi.org/10.1006/BBRC.2001.5793)

[2. (Franz1998Binding) Cornelia Franz, Isabelle Durussel, Jos A. Cox, Beat W. Schäfer, and Claus W. Heizmann. Binding of ca2+ and zn2+ to human nuclear s100a2 and mutant proteins. Journal of Biological Chemistry, 273(30):18826–18834, July 1998. URL: http://dx.doi.org/10.1074/jbc.273.30.18826, doi:10.1074/jbc.273.30.18826. This article has 40 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.273.30.18826)

[3. (Wolf2010S100A2) Susann Wolf, Cathleen Haase-Kohn, and Jens Pietzsch. S100a2 in cancerogenesis: a friend or a foe? Amino Acids, 41(4):849–861, June 2010. URL: http://dx.doi.org/10.1007/s00726-010-0623-2, doi:10.1007/s00726-010-0623-2. This article has 44 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00726-010-0623-2)

[4. (Hountis2014S100A2) Panagiotis Hountis, Dimitrios Matthaios, Marios Froudarakis, Demosthenes Bouros, and Stylianos Kakolyris. S100a2 protein and non-small cell lung cancer. the dual role concept. Tumor Biology, 35(8):7327–7333, May 2014. URL: http://dx.doi.org/10.1007/s13277-014-2117-4, doi:10.1007/s13277-014-2117-4. This article has 22 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s13277-014-2117-4)

[5. (Hatthakarnkul2023Protein) Phimmada Hatthakarnkul, Aula Ammar, Kathryn A. F. Pennel, Leah Officer-Jones, Silvia Cusumano, Jean A. Quinn, Amna Ahmed Mohemmed Matly, Peter G. Alexander, Jennifer Hay, Ditte Andersen, Gerard Lynch, Hester C. van Wyk, Noori Maka, Donald C. McMillan, John Le Quesne, Chanitra Thuwajit, and Joanne Edwards. Protein expression of s100a2 reveals it association with patient prognosis and immune infiltration profile in colorectal cancer. Journal of Cancer, 14(10):1837–1847, 2023. URL: http://dx.doi.org/10.7150/jca.83910, doi:10.7150/jca.83910. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.7150/jca.83910)

[6. (Koch2007Implications) Michael Koch, Shibani Bhattacharya, Torsten Kehl, Mario Gimona, Milan Vašák, Walter Chazin, Claus W. Heizmann, Peter M.H. Kroneck, and Günter Fritz. Implications on zinc binding to s100a2. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1773(3):457–470, March 2007. URL: http://dx.doi.org/10.1016/j.bbamcr.2006.12.006, doi:10.1016/j.bbamcr.2006.12.006. This article has 46 citations.](https://doi.org/10.1016/j.bbamcr.2006.12.006)

[7. (Koch2012The) Michael Koch and Günter Fritz. The structure of ca2+‐loaded s100a2 at 1.3‐å resolution. The FEBS Journal, 279(10):1799–1810, March 2012. URL: http://dx.doi.org/10.1111/j.1742-4658.2012.08556.x, doi:10.1111/j.1742-4658.2012.08556.x. This article has 9 citations.](https://doi.org/10.1111/j.1742-4658.2012.08556.x)

[8. (ZHAO2013Clinical) YING ZHAO, TIAN-BIAO ZHANG, and QIANG WANG. Clinical significance of altered s100a2 expression in gastric cancer. Oncology Reports, 29(4):1556–1562, January 2013. URL: http://dx.doi.org/10.3892/or.2013.2236, doi:10.3892/or.2013.2236. This article has 10 citations and is from a peer-reviewed journal.](https://doi.org/10.3892/or.2013.2236)

[9. (Li2021Prognostic) Xiaomin Li, Ning Qiu, and Qijuan Li. Prognostic values and clinical significance of s100 family member’s individualized mrna expression in pancreatic adenocarcinoma. Frontiers in Genetics, November 2021. URL: http://dx.doi.org/10.3389/fgene.2021.758725, doi:10.3389/fgene.2021.758725. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fgene.2021.758725)

[10. (Koch2008Crystal) Michael Koch, Joachim Diez, and Günter Fritz. Crystal structure of ca2+-free s100a2 at 1.6-å resolution. Journal of Molecular Biology, 378(4):933–942, May 2008. URL: http://dx.doi.org/10.1016/j.jmb.2008.03.019, doi:10.1016/j.jmb.2008.03.019. This article has 27 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jmb.2008.03.019)

[11. (Gonzalez2020Role) Laura L. Gonzalez, Karin Garrie, and Mark D. Turner. Role of s100 proteins in health and disease. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1867(6):118677, June 2020. URL: http://dx.doi.org/10.1016/j.bbamcr.2020.118677, doi:10.1016/j.bbamcr.2020.118677. This article has 193 citations.](https://doi.org/10.1016/j.bbamcr.2020.118677)

[12. (Deshpande2000Biochemical) Rohini Deshpande, Timothy L. Woods, Jian Fu, Tong Zhang, Stefan W. Stoll, and James T. Elder. Biochemical characterization of s100a2 in human keratinocytes: subcellular localization, dimerization, and oxidative cross-linking11portions of this work were presented at the annual meeting of the society for investigative dermatology, washington, dc, april, 1997. Journal of Investigative Dermatology, 115(3):477–485, September 2000. URL: http://dx.doi.org/10.1046/J.1523-1747.2000.00078.X, doi:10.1046/j.1523-1747.2000.00078.x. This article has 59 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1046/J.1523-1747.2000.00078.X)

[13. (SantamariaKisiel2006Calciumdependent) Liliana Santamaria-Kisiel, Anne C. Rintala-Dempsey, and Gary S. Shaw. Calcium-dependent and -independent interactions of the s100 protein family. Biochemical Journal, 396(2):201–214, May 2006. URL: http://dx.doi.org/10.1042/bj20060195, doi:10.1042/bj20060195. This article has 467 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1042/bj20060195)

[14. (Naz2013Protumorigenic) Sarwat Naz, Mohsin Bashir, Prathibha Ranganathan, Priyanka Bodapati, Vani Santosh, and Paturu Kondaiah. Protumorigenic actions of s100a2 involve regulation of pi3/akt signaling and functional interaction with smad3. Carcinogenesis, 35(1):14–23, August 2013. URL: http://dx.doi.org/10.1093/carcin/bgt287, doi:10.1093/carcin/bgt287. This article has 34 citations and is from a peer-reviewed journal.](https://doi.org/10.1093/carcin/bgt287)