Three-Dimensional Solution Structure of a Unique S100 Protein

by Vaithiyalingam, Sivaraja; Yu, Chin; Thallapuranam, Suresh Kumar

S100A13 is a homodimeric protein that belongs to the S100 subfamily of EF-hand Ca2+-binding proteins. S100A13 exhibits unique phys. and functional properties not obsd. in other members of the S100 family. S100A13 is crucial for the non-classical export of acidic fibroblast growth factors (FGFs-1), which lack signal peptide at their N-terminal end. In the present study, we report the three-dimensional soln. structure of Ca2+-bound S100A13 using a variety of 3D NMR expts. The structure of S100A13 is globular with four helixes and an antiparallel beta-sheet in each subunit. The dimer interface is formed mainly by an antiparallel arrangement of helixes H1, H1', H4 and H4'. Isothermal titrn. calorimetry (ITC) expts. show that S100A13 binds non-cooperatively to 4 calcium ions. Prominent differences exist between the three-dimensional structures of S100A13 and other S100 proteins. The hydrophobic pocket that largely contributes to protein-protein interactions in other S100 proteins, is absent in S100A13. The structure of S100A13 is characterized by a large patch of neg. charged residues flanked by dense cationic clusters contributed largely by the pos. charged residues located at the C-terminal end. Results of ITC expts. reveal that S100A13 lacking the C-terminal segment (residues 88 to 98) fails to bind FGF-1. The three-dimensional structure of S100A13 not only provides useful clues on its role in the non-classical export of signal peptide-less proteins such as FGF-1 but also paves way for the rational design of drugs against FGF-induced tumors.