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

• Published in: Structure (London) 1998-02, Vol.6 (2), p.211-222
• Main Authors: Smith, Steven P, Shaw, Gary S
• Format: Article
• Language: English
• Subjects: Amino Acids - chemistry; Animals; Apoproteins - chemistry; Calbindins; Calcium - chemistry; Calcium-binding protein; Calcium-Binding Proteins - chemistry; Cattle; Cell Cycle Proteins; conformational change; Dimerization; human S100B; Humans; Nerve Growth Factors - chemistry; NMR; Nuclear Magnetic Resonance, Biomolecular; Protein Conformation; Protein Structure, Secondary; Rats; S100 Calcium Binding Protein A6; S100 Calcium Binding Protein beta Subunit; S100 Calcium Binding Protein G - chemistry; S100 Proteins; solution structure; Surface Properties
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/S0969-2126(98)00022-7

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 (Ca 2+–100B) has been determined by heteronuclear NMR spectroscopy. Ca 2+–S100B forms a well defined globular structure comprising four EF-hand calcium-binding sites and an extensive hydrophobic dimer interface. A comparison of Ca 2+–S100B with apo S100B and Ca 2+–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.