Calcium Regulates S100A12 Zinc Sequestration by Limiting Structural Variations.

Antimicrobial proteins such as S100A12 and S100A8/A9 are highly expressed and secreted by neutrophils during infection and participate in human immune response by sequestering transition metals. At neutral pH, S100A12 sequesters Zn with nanomolar affinity, which is further enhanced upon calcium binding. We investigated the pH dependence of human S100A12 zinc sequestration by using Co as a surrogate. Apo-S100A12 exhibits strong Co binding between pH 7.0 and 10.0 that progressively diminishes as the pH is decreased to 5.3. Ca -S100A12 can retain nanomolar Co binding up to pH 5.7. NMR spectroscopic measurements revealed that calcium binding does not alter the side-chain protonation of the Co /Zn binding histidine residues. Instead, the calcium-mediated modulation is achieved by restraining pH-dependent conformational changes to EF loop 1, which contains Co /Zn binding Asp25. This calcium-induced enhancement of Co /Zn binding might assist in the promotion of antimicrobial activities in humans by S100 proteins during neutrophil activation under subneutral pH conditions.