Function and inhibition of the metastasis and inflammation promoting protein, S100A4
S100A4 / metastasin is an intensively studied member of the Ca2+-binding S100 protein family. It is an important player in tumor metastasis and chronic inflammation. Both physiological and pathological functions of S100A4 are related to migration and invasive phenotype of the cells.
Both the apo- as well as the Ca2+-bound form of S100A4 is homodimer. S100A4 functions through protein-protein interactions. Its cell motility promoting function is related to its binding to the C- terminal end of the heavy chain of non-muscle myosin 2A (NM2A). NM2A is responsible for the retrograde flow of the growing actin filaments at the leading edge of the cell. S100A4 binding to NM2A leads to dissociation of the NM2A filaments halting the retrograde flow and this way promoting cell protrusiveness and migration.
Recently we discovered a novel interaction topology in the S100 family. In a sharp contrast to the dimer-dimer interaction characteristic to the family, in our crystal structure one S100A4 dimer binds to a single heavy chain segment of NM2A. The S100A4 binding site overlaps with a coiled-coil region essential for filament formation therefore complex formation leads to filament dissociation. Phosphorylation of a serine residue at the intrinsically unstructured tail piece of NM2A outside of the S100A4 binding site inhibits both S100A4-binding and filament-formation.
Another important intracellular binding partner of S100A4 is the p53 tumor suppressor protein. Several publications report that formation of the above complex promotes survival of cancerous cells.
Our preliminary studies suggest that similarly to the S100A4-NM2A complex the S100A4-p53 complex is also asymmetrical.
In the frame of the MEDinPROT program we attempt to decipher the molecular details of formation and stability of the above complexes based on a combination of biophysical measurements, structural bioinformatics, NMR spectroscopy and directed protein evolution. We pay special attention to the functional roles of the intrinsically unstructured tailpiece of NM2A.
Besides gathering answers for fundamental scientific questions we also aim to develop antagonist peptides that - by blocking the protein-protein interactions of S100A4 - inhibit the metastasis and inflammation promoting function of this protein.
Andrea Bodor - Lajos Kalmár - László Nyitray - Gábor Pál