S100 protein
ContentsFunctionS100 proteins are calcium-binding proteins (CBP) found in vertebrates and contain 2 helix-loop-helix calcium binding sites. S100 name is derived from their being 100% soluble in ammonium sulfate. There are at least 21 S100 proteins. Most S100 proteins undergo conformational change upon calcium binding[1]. RelevanceS100-A2, S100-A3, S100-A5, S100-A7, S100-A8, S100-A9, S100-A14, S100-A15, S100-A16 and S100-P are over expressed on bladder cancer while S100-A1, S100-A4 and S100-B are under expressed[2]. S100-A12 is the most significant marker for psoriasis disease activity[3]. Various S100 proteins change this expression in skin and sweat glands tumors[4]. Solution structure and dynamics of human S100A14 [5]Human S100A14 is a member of the EF-hand calcium-binding protein family that has only recently been described in its functional and pathological properties. The protein is overexpressed in a variety of tumor cells and it has been shown to trigger receptor for advanced glycation end products (RAGE)-dependent signaling in cell cultures. The protein has a high degree of sequence homology with S100A13 although it exhibits a negligible affinity for calcium(II) ions and undergoes aggregation and precipitation in the presence of zinc(II) or copper(II) ions. The lack of two ligands in the canonical EF-hand calcium(II)-binding site explains the negligible affinity for calcium(II) in solution, while the exposed cysteines and histidine account for the observed precipitation in the presence of zinc(II) or copper(II) ions. Some residues, responsible for the binding of calcium(II) in S100A13 as well as in other S100 proteins, are mutated in S100A14. The solution structure of homodimeric S100A14 (monomer A is in mediumslateblue and monomer B is in deeppink) in the apo state at physiological temperature shows close structural similarities with the C-terminal domain of the myosin light chains and folds in a ‘semi-open’ conformation, with helices III and IV showing a X-shaped offset arrangement and helices II and III showing a high number of interactions creating a V-shaped arrangement.  The interacting aromatic residues in helix I (Phe-29) and helix IV (Phe-81, Phe-84, Trp-85) stabilize the interhelical orientation The most remarkable feature of this structural conformation involves the packing of the helices that is reduced with respect to the ‘closed’ structures of the S100 proteins but is still sizably larger than the corresponding ‘open’ structures. At the same time, the analysis of the electrostatic potential surface suggests that the S100A14 is permanently activated and it is not calcium(II) regulated. Structural characterization of human S100A16, a low-affinity calcium binder [6]S100A16 is a special member of the S100 class of calcium binding proteins, because it performs a conformational change upon calcium(II) binding much smaller than experienced by most S100 proteins. This was observed after determination of the solution structures of apo and calcium(II)-bound S100A16 and the crystal structure of apo S100A16. The likely reason for minimal conformational change in S100A16 is the lower calcium binding affinity and stronger hydrophobic interaction between helix III and IV present in this protein with respect to other S100 proteins. Another characteristic of S100A16 is that the helix IV has the same length in both apo and calcium(II) forms because of the presence of a Gly-Gly-Ile-Thr-Gly-Pro sequence motif in helix IV. Based on the available structures of S100 members, we analyzed and summarized all their conformational changes due to calcium(II) binding by a principal component analysis. Calcium binding was proved by both NMR titration and Isothermal Titration Calorimetry (ITC) experiments. Even if the important Glu residue in the last position of first EF-hand calcium binding loop is missing, these experimental data indicated that S100A16 can still bind one calcium(II) ion in such loop. NMR relaxation studies showed that the first calcium binding loop and the beginning of the second helix are the most flexible regions in both the apo and calcium(II)-bound S100A16. Although the biological function of S100A16 is still unclear yet, these structural and dynamic properties can provide useful information for further functional studies. 3D Structures of S100 proteins
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