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-bindi ng protein superfamily, The protein has been implicated in cellular pr ocesses such as cell differentiation and growth, plays a role in cytos keletal structure and function, and may have a role in neuropathologic al diseases, such as Alzheimers, The effects of S100B are mediated via its interaction with target proteins, While several studies have sugg ested that this interaction is propagated through a calcium-induced co nformational change, leading to the exposure of a hydrophobic region o f S100B, the molecular details behind this structural alteration remai n unclear, Results: The solution structure of calcium-saturated human S100B (Ca2+-S100B) has been determined by heteronuclear NMR spectrosco py. Ca2+-S100B forms a well defined globular structure comprising four EF-hand calcium-binding sites and an extensive hydrophobic dimer inte rface. A comparison of Ca2+-S100B with apo S100B and Ca2+-calbindin D- 9k indicates that while calcium-binding to S100B results in little cha nge 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 drama tic change in the position of helix III relative to the other helices. Conclusions: The calcium-induced reorientation of calcium-binding sit e II results in the increased exposure of several hydrophobic residues in helix IV and the linker region. While following the general mechan ism of calcium modulatory proteins, whereby a hydrophobic target site is exposed, the 'calcium switch' observed in S100B appears to be uniqu e from that of other EF-hand proteins and may provide insights into ta rget specificity among calcium modulatory proteins.