Joining S100 proteins and migration:for better or for worse, in sickness and in health

The vast diversity of S100 proteins has demonstrated a multitude of biological correlations with cell growth, cell differentiation and cell survival in numerous physiological and pathological conditions in all cells of the body. This review summarises some of the reported regulatory functions of S100 proteins (namely S100A1, S100A2, S100A4, S100A6, S100A7, S100A8/S100A9, S100A10, S100A11, S100A12, S100B and S100P) on cellular migration and invasion, established in both culture and animal model systems and the possible mechanisms that have been proposed to be responsible. These mechanisms involve intracellular events and components of the cytoskeletal organisation (actin/myosin filaments, intermediate filaments and microtubules) as well as extracellular signalling at different cell surface receptors (RAGE and integrins). Finally, we shall attempt to demonstrate how aberrant expression of the S100 proteins may lead to pathological events and human disorders and furthermore provide a rationale to possibly explain why the expression of some of the S100 proteins (mainly S100A4 and S100P) has led to conflicting results on motility, depending on the cells used. © 2013 Springer Basel

Intramolecular Interactions versus Hydration Effects on <i>p</i>‑Guanidinoethyl-phenol Structure and p<i>K</i>_a Values

We analyze the structure, hydration, and p<i>K</i>_a values of <i>p</i>-guanidinoethyl-phenol through a combined experimental and theoretical study. These issues are relevant to understand the mechanism of action of the tetrameric form, the antibacterial compound tetra-<i>p</i>-guanidinoethyl-calix­[4]­arene (Cx1). The investigated system can also be useful to model other pharmaceutical drugs bearing a guanidine function in the vicinity of an ionizable group and the effect of arginine on the p<i>K</i>_a of vicinal ionizable residues (in particular tyrosine) in peptides. The <i>p</i>-guanidinoethyl-phenol monomer (mCx1) has two ionizable groups. One important particularity of this system is that it exhibits high molecular flexibility that potentially leads to enhanced stabilization in folded structures by direct, strong Coulombic interactions between the ionizable groups. The first p<i>K</i>_a corresponding to ionization of the −OH group has experimentally been shown to be only slightly different from usual values in substituted phenols. However, because of short-range Coulombic interactions, the role of intramolecular interactions and solvation effects on the acidities of this compound is expected to be important and it has been analyzed here on the basis of theoretical calculations. We use a discrete-continuum solvation model together with quantum-mechanical calculations at the B3LYP level of theory and the extended 6-311+G­(2df,2p) basis set. Both intra- and intermolecular effects are very large (∼70 kcal/mol) but exhibit an almost perfect compensation, thus explaining that the actual p<i>K</i>_a of mCx1 is close to free phenol. The same compensation of environmental effects applies to the second p<i>K</i>_a that concerns the guanidinium group. Such a p<i>K</i>_a could not be determined experimentally with standard titration techniques and in fact the theoretical study predicts a value of 14.2, that is, one unit above the p<i>K</i>_a of the parent ethyl-guanidinium molecule