# S100A9

## Overview
S100A9 is a gene that encodes the S100 calcium-binding protein A9, a member of the S100 family of proteins characterized by their EF-hand calcium-binding motifs. The protein, also known as MRP14, plays a significant role in the regulation of inflammatory processes and immune responses. It is predominantly expressed in myeloid cells and often forms a heterodimer with S100A8, known as calprotectin, which is involved in various cellular functions, including calcium sensing, cytoskeleton rearrangement, and antimicrobial activity. S100A9 is implicated in the pathogenesis of several diseases, including cancer, cardiovascular diseases, and inflammatory disorders, due to its role in modulating immune cell recruitment and activation (Wang2018S100A8A9; Donato2012Functions; Ostrand-Rosenberg2023The).

## Structure
The S100A9 protein, also known as MRP14, is a member of the S100 family of calcium-binding proteins. It is characterized by two EF-hand motifs, which are helix-loop-helix structures responsible for calcium binding. The N-terminal EF-hand consists of 14 amino acids, while the C-terminal EF-hand comprises 12 amino acids and has a higher affinity for calcium (Kerkhoff1998Novel; Itou2002The). The protein's primary structure includes a single cysteine residue and lacks a signal or membrane anchor sequence (Kerkhoff1998Novel).

The secondary structure of S100A9 includes four alpha-helices, forming the EF-hand motifs. The tertiary structure involves the folding of these helices, with a hydrophobic cluster formed in the interior, crucial for target binding (Itou2002The). The C-terminal region is noted for its flexibility, which is functionally significant for interacting with various targets (Itou2002The).

In terms of quaternary structure, S100A9 can form homodimers or heterodimers with S100A8, known as calprotectin. This dimerization is calcium-dependent and plays a role in inflammatory processes (Itou2002The). Post-translational modifications of S100A9 include acetylation and phosphorylation (Kerkhoff1998Novel).

## Function
S100A9, a member of the S100 protein family, plays a crucial role in various cellular processes in healthy human cells. It primarily functions as a calcium sensor, participating in cytoskeleton rearrangement and arachidonic acid metabolism, which are essential for cell migration and other cellular activities (Wang2018S100A8A9). S100A9 often forms a heterodimer with S100A8, known as calprotectin, which acts as a cytoplasmic Ca2+ sensor linking calcium influx to phagosomal reactive oxygen species (ROS) production, crucial for effective phagocytosis (Donato2012Functions).

The S100A8/S100A9 complex is involved in the regulation of myeloid cell differentiation by inhibiting casein kinase I and II, and it plays a role in microtubule polymerization and F-actin cross-linking, aiding in cell migration, degranulation, and phagocytosis (Donato2012Functions). It also has antimicrobial properties, particularly against fungi and Staphylococcus aureus, through zinc and manganese chelation (Donato2012Functions).

S100A9 is active in both the cytoplasm and extracellular space, where it contributes to the recruitment of leukocytes and modulation of inflammatory responses. It is involved in the regulation of oxidative bursts in neutrophils and can influence the migration of neutrophils and other cell types (Wang2018S100A8A9; Donato2012Functions).

## Clinical Significance
Alterations in the expression of the S100A9 gene are associated with various diseases, particularly those involving inflammation and cancer. In cardiovascular diseases, the S100A8/A9 complex is implicated in atherogenesis, contributing to the development of atherosclerotic plaques by recruiting and activating neutrophils and monocytes in the arterial wall. Elevated levels of S100A8/A9 correlate with larger atherosclerotic lesions and increased inflammation in diabetic conditions, and high plasma concentrations are linked to acute cardiovascular events (Schiopu2013S100A8).

In cancer, S100A9 is overexpressed in many solid tumors and is associated with tumor progression and metastasis. It plays a role in the tumor microenvironment by driving the accumulation and function of myeloid-derived suppressor cells (MDSCs), which suppress antitumor immunity. Elevated levels of S100A9 are linked to poor prognosis in cancers such as prostate, gastric, and glioblastoma (Ostrand-Rosenberg2023The).

S100A9 is also involved in inflammatory diseases like rheumatoid arthritis, cystic fibrosis, and chronic bronchitis, where its elevated levels correlate with disease activity. It acts as a marker for monitoring inflammation and is involved in the transport of arachidonic acid, crucial for the inflammatory response (Nacken2003S100A9S100A8:).

## Interactions
S100A9, a calcium-binding protein, participates in various interactions with other proteins and nucleic acids, playing a significant role in inflammatory processes and cancer. It forms homodimers and heterodimers, most notably with S100A8, creating a complex known as calprotectin. This heterodimer is highly resistant to proteases and is prevalent in biological interactions (Markowitz2013Review). S100A9 interacts with several receptors, including RAGE and TLR4-MD2, which are crucial for signaling pathways like MAPK and NF-κB in cancer cells (Markowitz2013Review). 

In the context of neurodegenerative diseases, S100A9 interacts with alpha-synuclein (α-syn), influencing its aggregation behavior. This interaction is enhanced by calcium ions and involves specific regions on both proteins, such as the N-terminal part of α-syn and the interface formed by Helix 1 and Helix 4 of S100A9 (Toleikis2022Interactions). S100A9 also interacts with S100A12, which can block its interaction with the RAGE V domain, potentially influencing inflammatory responses (Katte2018Blocking). These interactions highlight S100A9's role in modulating inflammatory and cancer-related pathways, as well as its potential involvement in neurodegenerative diseases.


## References


[1. (Wang2018S100A8A9) Siwen Wang, Rui Song, Ziyi Wang, Zhaocheng Jing, Shaoxiong Wang, and Jian Ma. S100a8/a9 in inflammation. Frontiers in Immunology, June 2018. URL: http://dx.doi.org/10.3389/fimmu.2018.01298, doi:10.3389/fimmu.2018.01298. This article has 881 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2018.01298)

[2. (Ostrand-Rosenberg2023The) Suzanne Ostrand-Rosenberg, Tom Huecksteadt, and Karl Sanders. The receptor for advanced glycation endproducts (rage) and its ligands s100a8/a9 and high mobility group box protein 1 (hmgb1) are key regulators of myeloid-derived suppressor cells. Cancers, 15(4):1026, February 2023. URL: http://dx.doi.org/10.3390/cancers15041026, doi:10.3390/cancers15041026. This article has 12 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cancers15041026)

[3. (Toleikis2022Interactions) Zigmantas Toleikis, Raitis Bobrovs, Agne Janoniene, Alons Lends, Mantas Ziaunys, Ieva Baronaite, Vytautas Petrauskas, Kristine Kitoka, Vytautas Smirnovas, and Kristaps Jaudzems. Interactions between s100a9 and alpha-synuclein: insight from nmr spectroscopy. International Journal of Molecular Sciences, 23(12):6781, June 2022. URL: http://dx.doi.org/10.3390/ijms23126781, doi:10.3390/ijms23126781. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms23126781)

[4. (Katte2018Blocking) Revansiddha Katte and Chin Yu. Blocking the interaction between s100a9 protein and rage v domain using s100a12 protein. PLOS ONE, 13(6):e0198767, June 2018. URL: http://dx.doi.org/10.1371/journal.pone.0198767, doi:10.1371/journal.pone.0198767. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0198767)

[5. (Nacken2003S100A9S100A8:) Wolfgang Nacken, Johannes Roth, Clemens Sorg, and Claus Kerkhoff. S100a9/s100a8: myeloid representatives of the s100 protein family as prominent players in innate immunity. Microscopy Research and Technique, 60(6):569–580, March 2003. URL: http://dx.doi.org/10.1002/jemt.10299, doi:10.1002/jemt.10299. This article has 265 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/jemt.10299)

[6. (Kerkhoff1998Novel) Claus Kerkhoff, Martin Klempt, and Clemens Sorg. Novel insights into structure and function of mrp8 (s100a8) and mrp14 (s100a9). Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1448(2):200–211, December 1998. URL: http://dx.doi.org/10.1016/s0167-4889(98)00144-x, doi:10.1016/s0167-4889(98)00144-x. This article has 194 citations.](https://doi.org/10.1016/s0167-4889(98)00144-x)

[7. (Itou2002The) Hiroshi Itou, Min Yao, Ikuko Fujita, Nobuhisa Watanabe, Masaki Suzuki, Jun Nishihira, and Isao Tanaka. The crystal structure of human mrp14 (s100a9), a ca2+-dependent regulator protein in inflammatory process. Journal of Molecular Biology, 316(2):265–276, February 2002. URL: http://dx.doi.org/10.1006/jmbi.2001.5340, doi:10.1006/jmbi.2001.5340. This article has 82 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1006/jmbi.2001.5340)

[8. (Donato2012Functions) R. Donato, B. R. Cannon, G. Sorci, F. Riuzzi, K. Hsu, D. J. Weber, and C. L. Geczy. Functions of s100 proteins. Current Molecular Medicine, 13(1):24–57, December 2012. URL: http://dx.doi.org/10.2174/15665240130104, doi:10.2174/15665240130104. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.2174/15665240130104)

[9. (Schiopu2013S100A8) Alexandru Schiopu and Ovidiu S. Cotoi. S100a8 and s100a9: damps at the crossroads between innate immunity, traditional risk factors, and cardiovascular disease. Mediators of Inflammation, 2013:1–10, 2013. URL: http://dx.doi.org/10.1155/2013/828354, doi:10.1155/2013/828354. This article has 191 citations and is from a peer-reviewed journal.](https://doi.org/10.1155/2013/828354)

[10. (Markowitz2013Review) Joseph Markowitz and William E. Carson. Review of s100a9 biology and its role in cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1835(1):100–109, January 2013. URL: http://dx.doi.org/10.1016/j.bbcan.2012.10.003, doi:10.1016/j.bbcan.2012.10.003. This article has 53 citations.](https://doi.org/10.1016/j.bbcan.2012.10.003)