Pathologies Involving the S100 Proteins and Rage

Abstract

The S100 proteins are exclusively expressed in vertebrates and are the largest subgroup within the superfamily of EF-hand Ca ²⁺ -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 Ca ²⁺ -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 (Ca ²⁺ , Zn ²⁺ and Cu ²⁺ ) 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 iscuss 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