Pathologies involving the S100 proteins and RAGE.
The S100 proteins are exclusively expressed in vertebrates and are the largest subgroup within the superfamily of EF-hand Ca2(+)-binding proteins Generally, S100 proteins are organized as tight homodimers (some as heterodimers). Each subunit is composed of a C-terminal, 'canonical' EF-hand, common to all EF-hand proteins, and a N-terminal, 'pseudo' EF-hand, characteristic of S100 proteins. Upon Ca2(+)-binding, the C-terminal EF-hand undergoes a large conformational change resulting in the exposure of a hydrophobic surface responsible for target binding A unique feature of this protein family is that some members are secreted from cells upon stimulation, exerting cytokine- and chemokine-like extracellular activities via the Receptor for Advanced Glycation Endproducts, RAGE. Recently, larger assemblies of some S100 proteins (hexamers, tetramers, octamers) have been also observed and are suggested to be the active extracellular species required for receptor binding and activation through receptor multimerization Most S100 genes are located in a gene cluster on human chromosome 1q21, a region frequently rearranged in human cancer The functional diversification of S100 proteins is achieved by their specific cell- and tissue-expression patterns, structural variations, different metal ion binding properties (Ca2+, Zn2+ and Cu2+) as well as their ability to form homo-, hetero- and oligomeric assemblies Here, we review the most recent developments focussing on the biological functions of the S100 proteins and we discuss the presently available S100-specific mouse models and their possible use as human disease models In addition, the S100-RAGE interaction and the activation of various cellular pathways will be discussed. Finally, the close association of S100 proteins with cardiomyopathy, cancer, inflammation and brain diseases is summarized as well as their use in diagnosis and their potential as drug targets to improve therapies in the future.
Heizmann
C W
CW
Division of Clinical Chemistry and Biochemistry, Department of Pediatrics, University of Zurich, Switzerland. Claus.Heizmann@kispi.unizh.ch
Ackermann
G E
GE
Galichet
A
A
D000818:Animals; D017306:Annexin A2 / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000502:physiology; D040501:Calgranulin A / Q000502:physiology; D040502:Calgranulin B / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology; D002630:Chemotactic Factors / Q000502:physiology; D020832:EF Hand Motifs; D006801:Humans; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D000075383:S100 Calcium Binding Protein A6; D000075023:S100 Calcium Binding Protein A7; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000737:chemistry / Q000502:physiology*; D000099248:S100 Calcium Binding Protein A10
D017306:Annexin A2; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D040502:Calgranulin B; D018797:Cell Cycle Proteins; D002630:Chemotactic Factors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000075383:S100 Calcium Binding Protein A6; D000075023:S100 Calcium Binding Protein A7; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10; C098997:S100A2 protein, human; C082356:S100A3 protein, human; C082355:S100A5 protein, human; C089242:S100A7 protein, human; C470944:S100a4 protein, mouse; C055351:S100A6 protein, human; C072337:S100A11 protein, human