One class of proteins that has been increasingly emerging as a potentially important group of both molecular key players and biomarkers in the etiology, progression, manifestation and therapy of various inflammatory, neurodegenerative, metabolic and neoplastic disorders is the S100 family. S100 proteins are small, acidic, calcium-binding proteins, characterized by the presence of two calcium-binding EF-hand motifs, and found exclusively in vertebrates. The first member was identified in the bovine nervous system by Moore (1965). The name S100 was derived from the observation of the protein fraction remaining soluble after precipitation with 100% saturated ammonium sulfate at neutral pH. Subsequent studies demonstrated that this fraction contained predominantly two proteins, S100A1 and S100B. Since the first isolation and characterization of these 2 S100 proteins, at least 23 additional proteins have been assigned as members of the S100 family in humans (Marenholz et al. 2004, 2006). Twenty-one of them (S100A1–S100A18, and the multidomain proteins trichohyalin, filaggrin and repetin) are coded by genes clustered at chromosome locus 1q21, known as the epidermal differentiation complex, while the other genes belonging to the subfamilies of S100B, S100P, S100Z and S100G are, respectively, located at chromosome loci 21q22, 4p16, 5q14 and Xp22 (Santamaria-Kisiel et al. 2006). S100 proteins form homodimer, heterodimer and even oligomeric molecular assemblies and are expressed in a tissueand cell-specific manner, suggesting that each S100 protein may perform different functions (Donato 1999; Fritz and Heizmann 2006). Functional complexity and diversification of S100 proteins have been further achieved by differences in localization, e.g., intracellularly in cytoplasm and/or nucleus, extracellularly in various body fluid compartments, by action as autocrine or paracrine effectors, and by exhibition of different affinities toward calcium ions resulting in various degrees of conformational change and modes of interaction with a whole host of specific target proteins (Donato 1999; Leclerc et al. 2009). Moreover, several S100 proteins are known to bind to other divalent metal ions, such as magnesium, zinc and the transition metal copper with high affinity, perhaps implicating them additionally in the homeostasis of toxic metals and related pathophysiological conditions (Moroz et al. 2009). All of these result in a tremendous spectrum of pleiotropic intraand extracellular functions. In this regard, through, e.g., inhibition of protein phosphorylation, regulation of transcriptional factors, modulation of enzyme activity and cytoskeletal dynamics, S100 proteins have been linked to vital cellular processes, including cell cycle regulation, cell growth and differentiation, transcription, cell motility and invasion, extracellular signal transduction and intercellular adhesion (Santamaria-Kisiel et al. 2006, Leclerc et al. 2009). Among natural targets of extracellular S100 proteins, the multiligand or pattern recognition receptor for advanced glycation end products (RAGE) has gained significant importance (Hofmann et al. 1999; Leclerc et al. 2009). RAGE is a signal transduction receptor of the immunoglobulin superfamily and was first described as a receptor for end products of non-enzymatic glycation and glycoxidation of proteins (Schmidt et al. 1992). Importantly, RAGE also transduces signals stimulated by non-glycated proteins that J. Pietzsch (&) Department of Radiopharmaceutical Biology, Institute of Radiopharmacy, Research Center Dresden-Rossendorf, POB 510119, 01314 Dresden, Germany e-mail: j.pietzsch@fzd.de
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Jan 9, 2012
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