|S100 calcium binding protein A7A|
PDB rendering based on 3psr.
|Symbols||; NICE-2; S100A15; S100A7L1; S100A7f|
Koebnerisin also known as protein S100-A7A (S100A7A), S100 calcium-binding protein A7-like 1 (S100A7L1) or S100 calcium-binding protein A15 (S100A15) is a protein that in humans is encoded by the S100A7A (alias:S100A15) gene.
S100 proteins are a diverse calcium-binding family that regulate fundamental cellular and extracellular processes including cell proliferation and differentiation, cell migration, and the antimicrobial host defense as antimicrobial peptides.
Koebnerisin (S100A15) was first identified upregulated in inflammation-prone psoriatic skin, suggesting involvement in the lesional phenotype of the disease, Koebner phenomenon. Today, the protein is of further interest because of its role in antimicrobial defence, innate immunity, epidermal cell maturation and epithelial tumorigenesis.
Epithelial homeostasis and antimicrobial host defence
Skin: In normal epidermis, koebnerisin (S100A15) is expressed by epidermal basal and differentiated keratinocytes, melanocytes, and Langerhans cells. Within the pilosebaceous unit, S100A15 is found in the inner and external root sheath and the basal layer of the sebaceous gland. In the dermis, koebnerisin (S100A15) is produced by dendritic cells smooth muscle cells and endothelial cells.
Breast: Koebnerisin (S100A15) is expressed by alveolar and small duct luminal cells and by epithelial-derived myoepithelial cells around acini and by surrounding blood vessels.
Koebnerisin (S100A15) functions as an antimicrobial peptide (AMP) reducing survival of E. coli and was strongly regulated by several bacterial components, such as P. aeruginosa and S. aureus. Thus, koebnerisin participates in the antimicrobial host defence of the skin and in the digestive tract of breast-feeding newborns.
Breast cancer: Koebnerisin (S100A15) is overexpressed in ER/PR negative tumors suggesting a regulation with tumor progression. The secreted koebnerisin (S100A15) acts as a chemoattractant, enhances inflammation and thus could drive breast carcinogenesis.
Koebnerisin (S100A15) is overexpressed in inflammatory skin diseases, such as psoriasis and eczema. It is regulated through Th1 and Th17 but not Th2 proinflammatory cytokines. When released into the extracellar space, koebnerisin (S100A15) induces inflammation. It acts as a chemoattractant for myeloid leukocytes through a pertussis toxin sensitive Gi protein coupled receptor. Koebnerisin (S100A15) amplifies inflammation with related psoriasin (S100A7) that is co-regulated and proinflammatory through RAGE.
Genomic organization and mRNA splice variants
Koebnerisin (S100A15) maps to the S100 gene cluster within the epidermal differentiation complex (EDC, chromosome 1q21) and reveals an unusual genomic organization compared to other S100 members. The two alternative mRNA-isoforms of koebnerisin share the same coding region, but show differences in composition and length of adjacent untranslated regions (S100A15-short (S): 0.5 kb vs. hS100A15-long (L): 4.4 kb). Both splice variants are differently regulated in inflammatory skin diseases suggesting usage of alternate promoters.
The amino acid sequence reveals a conserved C-terminal and a variant N-terminal EF-hand typical for S100 proteins (101 amino acids, 11.305 Da, calculated pI of 7.57 kDa). Compared to most S100 proteins, koebnerisin (S100A15) is basic.
Koebnerisin (S100A15) has lately evolved by gene duplications within the Epidermal Differentiation Complex (EDC, chromosome 1q21) during primate evolution forming a novel S100 subfamily together with Psoriasin (S100A7). Therefore, koebnerisin is almost identical to psoriasin in sequence (>90%). Despite their high homology, koebnerisin (S100A15) and psoriasin (S100A7) are distinct in tissue distribution, regulation, structure and function and, thus exemplary for the diversity within the S100 family. Their different properties are compelling reasons to discriminate S100A15 (koebnerisin) and S100A7 (psoriasin) in epithelial homeostasis, inflammation and cancer.
Koebnerisin (S100A15) and psoriasin (S100A7) share a common protein in mice encoded by the S100a7a15 (alias: mS100A7, mS100A15, mS100a7a) gene. It can be used to study the significance of the corresponding human proteins for epidermal maturation, inflammation and carcinogenesis.
- "Entrez Gene: S100 calcium binding protein A7A".
- Wolf R, Mirmohammadsadegh A, Walz M, Lysa B, Tartler U, Remus R, Hengge U, Michel G, Ruzicka T (October 2003). "Molecular cloning and characterization of alternatively spliced mRNA isoforms from psoriatic skin encoding a novel member of the S100 family". FASEB J. 17 (13): 1969–71. doi:10.1096/fj.03-0148fje. PMID 12923069.
- Wolf R, Ruzicka T, Yuspa SH (July 2010). "Novel S100A7 (psoriasin)/S100A15 (koebnerisin) subfamily: highly homologous but distinct in regulation and function". Amino Acids 41 (4): 789–96. doi:10.1007/s00726-010-0666-4. PMID 20596736.
- Zwicker S, Bureik D, Ruzicka T, Wolf R (March 2012). "[Friend or Foe?--Psoriasin and Koebnerisin: multifunctional defence molecules in skin differentiation, tumorigenesis and inflammation]". Dtsch. Med. Wochenschr. (in German) 137 (10): 491–4. doi:10.1055/s-0031-1299015. PMID 22374659.
- Wolf R, Howard OM, Dong HF, Voscopoulos C, Boeshans K, Winston J, Divi R, Gunsior M, Goldsmith P, Ahvazi B, Chavakis T, Oppenheim JJ, Yuspa SH (July 2008). "Chemotactic activity of S100A7 (Psoriasin) is mediated by the receptor for advanced glycation end products and potentiates inflammation with highly homologous but functionally distinct S100A15". J. Immunol. 181 (2): 1499–506. PMC 2435511. PMID 18606705.
- Wolf R, Voscopoulos C, Winston J, Dharamsi A, Goldsmith P, Gunsior M, Vonderhaar BK, Olson M, Watson PH, Yuspa SH (May 2009). "Highly homologous hS100A15 and hS100A7 proteins are distinctly expressed in normal breast tissue and breast cancer". Cancer Lett. 277 (1): 101–7. doi:10.1016/j.canlet.2008.11.032. PMC 2680177. PMID 19136201.
- Büchau AS, Hassan M, Kukova G, Lewerenz V, Kellermann S, Würthner JU, Wolf R, Walz M, Gallo RL, Ruzicka T (November 2007). "S100A15, an antimicrobial protein of the skin: regulation by E. coli through Toll-like receptor 4". J. Invest. Dermatol. 127 (11): 2596–604. doi:10.1038/sj.jid.5700946. PMID 17625598.
- Wolf, R; Mascia, F; Dharamsi, A; Howard, OM; Cataisson, C; Bliskovski, V; Winston, J; Feigenbaum, L; Lichti, U; Ruzicka, T; Chavakis, T; Yuspa, SH (8 December 2010). "Gene from a psoriasis susceptibility locus primes the skin for inflammation.". Science translational medicine 2 (61): 61ra90. doi:10.1126/scitranslmed.3001108. PMID 21148126.
- Wolf R, Lewerenz V, Büchau AS, Walz M, Ruzicka T (August 2007). "Human S100A15 splice variants are differentially expressed in inflammatory skin diseases and regulated through Th1 cytokines and calcium". Exp. Dermatol. 16 (8): 685–91. doi:10.1111/j.1600-0625.2007.00587.x. PMID 17620096.
- Hegyi Z, Zwicker S, Bureik D, Peric M, Koglin S, Batycka-Baran A, Prinz JC, Ruzicka T, Schauber J, Wolf R (May 2012). "Vitamin D analog calcipotriol suppresses the Th17 cytokine-induced proinflammatory S100 "alarmins" psoriasin (S100A7) and koebnerisin (S100A15) in psoriasis". J. Invest. Dermatol. 132 (5): 1416–24. doi:10.1038/jid.2011.486. PMID 22402441.
- Kulski JK, Lim CP, Dunn DS, Bellgard M (April 2003). "Genomic and phylogenetic analysis of the S100A7 (Psoriasin) gene duplications within the region of the S100 gene cluster on human chromosome 1q21". J. Mol. Evol. 56 (4): 397–406. doi:10.1007/s00239-002-2410-5. PMID 12664160.
- Wolf R, Voscopoulos CJ, FitzGerald PC, Goldsmith P, Cataisson C, Gunsior M, Walz M, Ruzicka T, Yuspa SH (July 2006). "The mouse S100A15 ortholog parallels genomic organization, structure, gene expression, and protein-processing pattern of the human S100A7/A15 subfamily during epidermal maturation". J. Invest. Dermatol. 126 (7): 1600–8. doi:10.1038/sj.jid.5700210. PMID 16528363.
- Murray JI, Tonkin ML, Whiting AL, Peng F, Farnell B, Cullen JT, Hof F, Boulanger MJ (2012). "Structural characterization of S100A15 reveals a novel zinc coordination site among S100 proteins and altered surface chemistry with functional implications for receptor binding". BMC Struct. Biol. 12: 16. doi:10.1186/1472-6807-12-16. PMC 3434032. PMID 22747601.
- Boeshans KM, Wolf R, Voscopoulos C, Gillette W, Esposito D, Mueser TC, Yuspa SH, Ahvazi B (May 2006). "Purification, crystallization and preliminary X-ray diffraction of human S100A15". Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 62 (Pt 5): 467–70. doi:10.1107/S1744309106012838. PMC 2219979. PMID 16682778.
- "Entrez Gene: S100a7a S100 calcium binding protein".