A novel calcium-sensitive switch revealed by the structure of human S100B in the calcium-bound form

Background: S100B is a homodimeric member of the EF-hand calcium-binding protein superfamily, The protein has been implicated in cellular processes such as cell differentiation and growth, plays a role in cytoskeletal structure and function, and may have a role in neuropathological diseases, such as Alzheimers, The effects of S100B are mediated via its interaction with target proteins, While several studies have suggested that this interaction is propagated through a calcium-induced conformational change, leading to the exposure of a hydrophobic region of S100B, the molecular details behind this structural alteration remain unclear, Results: The solution structure of calcium-saturated human S100B (Ca2+-S100B) has been determined by heteronuclear NMR spectroscopy. Ca2+-S100B forms a well defined globular structure comprising four EF-hand calcium-binding sites and an extensive hydrophobic dimer interface. A comparison of Ca2+-S100B with apo S100B and Ca2+-calbindin D-9k indicates that while calcium-binding to S100B results in little change in the site I EF-hand, it induces a backbone reorientation of the N terminus of the site II EF-hand, This reorientation leads to a dramatic change in the position of helix III relative to the other helices. Conclusions: The calcium-induced reorientation of calcium-binding site II results in the increased exposure of several hydrophobic residues in helix IV and the linker region. While following the general mechanism of calcium modulatory proteins, whereby a hydrophobic target site is exposed, the 'calcium switch' observed in S100B appears to be unique from that of other EF-hand proteins and may provide insights into target specificity among calcium modulatory proteins.