S100A2 is an EF-hand calcium ion (Ca2+)-binding protein that activates the tumour suppressor p53. In order to understand the molecular mechanisms underlying the Ca2+-induced activation of S100A2, the structure of Ca2+-bound S100A2 was determined at 1.3 Å resolution by X-ray crystallography. The structure was compared with Ca2+-free S100A2 and with other S100 proteins. Binding of Ca2+ to S100A2 induces small structural changes in the N-terminal EF-hand, but a large conformational change in the C-terminal EF-hand, reorienting helix III by approximately 90°. This movement is accompanied by the exposure of a hydrophobic cavity between helix III and helix IV that represents the target protein interaction site. This molecular reorganization is associated with the breaking and new formation of intramolecular hydrophobic contacts. The target binding site exhibits unique features; in particular, the hydrophobic cavity is larger than in other Ca2+-loaded S100 proteins. The structural data underline that the shape and size of the hydrophobic cavity are major determinants for target specificity of S100 proteins and suggest that the binding mode for S100A2 is different from that of other p53-interacting S100 proteins.
Structural data are available in the Protein Data Bank database under the accession number 4DUQ
Structured digital abstract