New perspectives on S100 proteins: a multi-functional Ca(2+)-, Zn(2+)- and Cu(2+)-binding protein family.
S100 proteins (16 members) show a very divergent pattern of cell- and tissue-specific expression, of subcellular localizations and relocations, of post-translational modifications, and of affinities for Ca2+, Zn2+, and Cu2+, consistent with their pleiotropic intra- and extracellular functions. Up to 40 target proteins are reported to interact with S100 proteins and for S100A1 alone 15 target proteins are presently known. Therefore it is not surprising that many functional roles have been proposed and that several human disorders such as cancer, neurodegenerative diseases, cardiomyopathies, inflammations, diabetes, and allergies are associated with an altered expression of S100 proteins. It is not unlikely that their biological activity in some cases is regulated by Zn2+ and Cu2+, rather than by Ca2+. Despite the numerous putative functions of S100 proteins, their three-dimensional structures of, e.g., S100B, S100A6, and S100A7 are surprisingly similar. They contain a compact dimerization domain whose conformation is rather insensitive to Ca2+ binding and two lateral alpha-helices III and III, which project outward of each subunit when Ca2+ is bound. Target docking depends on the two hydrophobic patches in front of the paired EF-hand generated by the binding of Ca2+. The selectivity in target binding is assured by the central linker between the two EF-hands and the C-terminal tail. It appears that the S100-binding domain in some target proteins contains a basic amphiphilic alpha-helix and that the mode of interaction and activation bears structural similarity to that of calmodulin.
Heizmann
C W
CW
Department of Pediatrics, University of Zurich, Switzerland.
Cox
J A
JA
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D009418:S100 Proteins / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015032:Zinc / Q000378:metabolism*; D016335:Zinc Fingers
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D009418:S100 Proteins; D003300:Copper; D015032:Zinc; D002118:Calcium