Encyclopedia of Metalloproteins

2013 Edition
| Editors: Robert H. Kretsinger, Vladimir N. Uversky, Eugene A. Permyakov

S100 Proteins

  • Rosario Donato
  • Carolyn L. Geczy
  • David J. Weber
Reference work entry
DOI: https://doi.org/10.1007/978-1-4614-1533-6_48


Most S100 proteins are Ca2+-binding proteins involved in Ca2+-signal transduction. They have a well-conserved EF-hand Ca2+-binding motif and a second atypical EF-hand. S100s form stable symmetric homodimers and in the presence of appropriate binding targets, dissociation constants for Ca2+-binding reach physiological levels. S100 proteins are generally constitutively expressed in a cell-specific manner. Several are induced by growth factors, cytokines, or Toll-like receptor (TLR) ligands, in processes associated with stress responses, an activated innate immune system, tumorigenesis, and/or tissue repair. In addition to functions as intracellular regulators, many S100 proteins act extracellularly and particular posttranslational modifications can promote changes in extracellular function. Receptors have been elusive, but include the receptor for advanced glycation end products (RAGE), N-glycans and TLRs.


Several classes of Ca2+-binding proteins have evolved from...

This is a preview of subscription content, log in to check access.


  1. Arumugam T, Logsdon CD (2010) S100P: a novel therapeutic target for cancer. Amino Acids 41:893–899.CrossRefPubMedGoogle Scholar
  2. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signaling: dynamics, homeostasis and remodeling. Nature Rev Mol Cell Biol 4:517–529.CrossRefGoogle Scholar
  3. Boye K, Maelandsmo GM (2010) S100A4 and metastasis: a small actor playing many roles. Am J Pathol 176:528–535.CrossRefPubMedGoogle Scholar
  4. Boyd JH, Kan B, Roberts H et al (2008) S100A8 and S100A9 mediate endotoxin-induced cardiomyocyte dysfunction via the receptor for advanced glycation end products. Circ Res 102:1239–1246.CrossRefPubMedGoogle Scholar
  5. Charpentier TH, Thompson LE, Liriano MA et al (2010) The effects of CapZ peptide (TRTK-12) binding to S100B-Ca2+ as examined by NMR and X-ray crystallography. J Mol Biol 396:1227–1243.CrossRefPubMedGoogle Scholar
  6. Carafoli E, Klee C (Eds) (1999) Calcium as a cellular regulator. New York: Oxford University Press.Google Scholar
  7. Corbin BD, Seeley EH, Raab A et al (2008) Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 319:962–965.CrossRefPubMedGoogle Scholar
  8. Dassan P, Keir G, Brown MM (2009) Criteria for a clinically informative serum biomarker in acute ischaemic stroke: a review of S100B. Cerebrovasc Dis, 27:295–302.CrossRefPubMedGoogle Scholar
  9. Donato R (2001) S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol 33:637–668.CrossRefPubMedGoogle Scholar
  10. Donato R (2007) RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins. Curr Mol Med 7:711–724.CrossRefPubMedGoogle Scholar
  11. Donato R, Sorci G, Riuzzi F et al (2009) S100B’s double life: intracellular regulator and extracellular signal. Biochim Biophys Acta 1793:1008–1022.CrossRefPubMedGoogle Scholar
  12. Ehrchen JM, Sunderkötter C, Foell D, Vogl T, Roth J (2009) The endogenous toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 86:557–566.CrossRefPubMedGoogle Scholar
  13. Ghavami S, Chitayat S, Hashemi M, et al (2009) S100A8/A9: a Janus-faced molecule in cancer therapy and tumorgenesis. Eur J Pharmacol 625:73–83.CrossRefPubMedGoogle Scholar
  14. Goyette J, Geczy CL. (2010) Inflammation-associated S100 proteins: new mechanisms that regulate function. Amino Acids 41:821–842.CrossRefPubMedGoogle Scholar
  15. Heizmann CW (2002) The multifunctional S100 protein family. Meth Mol Biol 172:69–80.Google Scholar
  16. Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2006) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 8:1369–1375.CrossRefPubMedGoogle Scholar
  17. Hofmann MA, Drury S, Fu C, et al (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97:889–901.CrossRefPubMedGoogle Scholar
  18. Hofmann Bowman MA, Wilk J, Heydemann A et al (2010) S100A12 mediates aortic wall remodeling and aortic aneurysm. Circ Res 106:145–154.CrossRefPubMedGoogle Scholar
  19. Hofmann Bowman MA, Gawdzik J, Bukhari U et al (2011) S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein e-null mice by activating an osteogenic gene regulatory program. Arterioscler Thromb Vasc Biol 31:337–344.CrossRefPubMedGoogle Scholar
  20. Kligman D, Hilt DC (1988) The S100 protein family. Trends Biochem Sci 13:437–443.CrossRefPubMedGoogle Scholar
  21. Lesniak W, Filipek A, Donato R (2009) S100a6. UCSD-Nat Molecule Page. doi:10.1038/mp.a002122.01.Google Scholar
  22. Lin J, Yang Q, Wilder PT et al (2010) The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma. J Biol Chem 285:27487–27498.CrossRefPubMedGoogle Scholar
  23. Loser K, Voskort M, Lueken A, et al (2010) The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells. Nat Med 16:713–717.CrossRefPubMedGoogle Scholar
  24. Marenholz I, Heizmann CW, Fritz G (2004) S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun 322:1111–1122.CrossRefPubMedGoogle Scholar
  25. Mocellin S, Zavagno G, Nitti D (2008) The prognostic value of serum S100B in patients with cutaneous melanoma: a meta-analysis. Int J Cancer 123:2370–2376.CrossRefPubMedGoogle Scholar
  26. Moews PC, Kretsinger RH (1975) Refinement of the structure of carp muscle calcium-binding parvalbumin by model building and difference Fourier analysis. J Mol Biol 91:201–225.CrossRefPubMedGoogle Scholar
  27. Mori T, Koyama N, Arendash GW et al (2010) Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer’s disease. Glia 58:300–314.PubMedGoogle Scholar
  28. Nukui T, Ehama R, Sakaguchi M et al (2008) S100A8/A9, a key mediator for positive feedback growth stimulation of normal human keratinocytes. J Cell Biochem 104:453–464.CrossRefPubMedGoogle Scholar
  29. Ostendorp T, Leclerc E, Galichet A et al (2007) Structural and functional insights into RAGE activation by multimeric S100B. EMBO J26:3868–3878.Google Scholar
  30. Permyakov EA, Kretsinger RH (2009) Cell signaling, beyond cytosolic calcium in eukaryotes. J Inorg Biochem 103:77–86.CrossRefPubMedGoogle Scholar
  31. Pietzsch JS, Hoppmann S (2009) Human S100A12: a novel key player in inflammation? Amino Acids 36:381–389.CrossRefPubMedGoogle Scholar
  32. Prosser BL, Wright NT, Hernandez-Ochoa EO et al (2008) S100A1 binds to the calmodulin-binding site of ryanodine receptor and modulates skeletal muscle excitation-contraction coupling. J Biol Chem 283:5046–5057.CrossRefPubMedGoogle Scholar
  33. Rescher U, Gerke V (2008) S100A10/p11: family, friends and functions. Pflugers Arch 455:575–582.CrossRefPubMedGoogle Scholar
  34. Rohde D, Ritterhoff J, Voelkers M et al (2010) S100A1: a multifaceted therapeutic target in cardiovascular disease. J Cardiovasc Transl Res 3:525–537.CrossRefPubMedGoogle Scholar
  35. Rothermundt M, Ahn JN, Jörgens S (2010) S100B in schizophrenia: an update. Gen Physiol Biophys 28:F76–F81.Google Scholar
  36. Rustandi RR, Baldisseri DM, Drohat AC, Weber DJ (1999) Structural changes in the C-terminus of Ca2+-bound rat S100B (ββ) upon binding to a peptide derived from the C-terminal regulatory domain of p53. Protein Sci 8:1743–1751.CrossRefPubMedGoogle Scholar
  37. Sparvero LJ, Asafu-Adjei D, Kang R et al (2009) RAGE (Receptor for advanced glycation endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med 7:17.CrossRefPubMedGoogle Scholar
  38. Strynadka NC, James MN (1989) Crystal structures of the helix-loop-helix calcium-binding proteins. Annu Rev Biochem, 58:951–998.CrossRefPubMedGoogle Scholar
  39. Tsoporis JN, Mohammadzadeh F, Parker TG (2010) Intracellular and extracellular effects of S100B in the cardiovascular response to disease. Cardiovasc Psychiatry Neurol 2010, 206073. doi:10.1155/2010/206073.PubMedGoogle Scholar
  40. Turovskaya O, Foell D, Sinha P et al (2009) RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis 29:2035–2043.CrossRefGoogle Scholar
  41. van Dieck J, Teufel DP, Jaulent AM et al (2009) Posttranslational modifications affect the interaction of S100 proteins with tumor suppressor p53. J Mol Biol 394:922–930.CrossRefPubMedGoogle Scholar
  42. van Lent PL, Grevers LC, Blom AB et al (2008) Stimulation of chondrocyte-mediated cartilage destruction by S100A8 in experimental murine arthritis. Arthritis Rheum 58:3776–3787.CrossRefPubMedGoogle Scholar
  43. Vogl T, Tenbrock K, Ludwig S et al (2007) Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med 13:1042–1049.CrossRefPubMedGoogle Scholar
  44. Warner-Schmidt JL, Chen EY, Zhang X et al (2010) A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry 68:528–535.CrossRefPubMedGoogle Scholar
  45. West NR, Watson PH (2010) S100A7 (psoriasin) is induced by the proinflammatory cytokines oncostatin-M and interleukin-6 in human breast cancer. Oncogene 29:2083–2092.CrossRefPubMedGoogle Scholar
  46. Wright NT, Prosser BL, Varney KM et al (2008) S100A1 and calmodulin compete for the same binding site on ryanodine receptor. J Biol Chem 283:26676–26683.CrossRefPubMedGoogle Scholar
  47. Yap KL, Ames JB, Swindells MB, Ikura M (1999) Diversity of conformational states and changes within the EF-hand protein superfamily. Proteins 37:499–507.CrossRefPubMedGoogle Scholar
  48. Zimmer DB, Wright SP, Weber DJ (2003) Molecular mechanisms of S100-target protein interactions. Microsc Res Tech 60:552–559.CrossRefPubMedGoogle Scholar
  49. Zimmer DB, Weber DJ (2010) The calcium-dependent interaction of S100B with its protein targets. Cardiovasc Psychiatry Neurol. doi:10.1155/2010/728052.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Rosario Donato
    • 1
  • Carolyn L. Geczy
    • 2
  • David J. Weber
    • 3
  1. 1.Department of Experimental Medicine and Biochemical SciencesUniversity of PerugiaPerugiaItaly
  2. 2.Inflammation and Infection Research Centre, School of Medical SciencesUniversity of New South WalesSydneyAustralia
  3. 3.Department of Biochemistry and Molecular BiologyUniversity of Maryland School of MedicineBaltimoreUSA