S100 and S100 fused-type protein families in epidermal maturation with special focus on S100A3 in mammalian hair cuticles

Epithelial Ca2+-regulation, which governs cornified envelope formation in the skin epidermis and hair follicles, closely coincides with the expression of S100A3, filaggrin and trichohyalin, and the post-translational modification of these proteins by Ca2+-dependent peptidylarginine deiminases. This review summarizes the current nomenclature and evolutional aspects of S100 Ca2+-binding proteins and S100 fused-type proteins (SFTPs) classified as a separate protein family with special reference to the molecular structure and function of S100A3 dominantly expressed in hair cuticular cells. Both S100 and SFTP family members are identified by two distinct types of Ca2+-binding loops in an N-terminal pseudo EF-hand motif followed by a canonical EF-hand motif. Seventeen members of the S100 protein family including S100A3 are clustered with seven related genes encoding SFTPs on human chromosome 1q21, implicating their association with epidermal maturation and diseases. Human S100A3 is characterized by two disulphide bridges and a preformed Zn2+-pocket, and may transfer Ca2+ ions to peptidylarginine deiminases after its citrullination-mediated tetramerization. Phylogenetic analysis utilizing current genome databases suggests that divergence of the S100A3 gene coincided with the emergence of hair, a defining feature of mammals, and that the involvement of S100A3 in epithelial Ca2+-cycling occurred as a result of a skin adaptation in terrestrial mammals.

► Summary of nomenclature and evolutional aspects of S100/SFTP protein families.
► Focused review of the molecular structure and function of S100A3.
► S100 Ca2+-modulating protein A3 transfers Ca2+ ions to PAD enzymes.
► Divergence of S100A3 coincided with the emergence of mammalian hair.
► S100A3 involves epithelial Ca2+-cycling as a result of a skin terrestrial adaptation.