Calcium Regulates S100A12 Zinc Sequestration by Limiting Structural Variations.

Area of Science:

• Biochemistry
• Immunology
• Structural Biology

Background:

• S100A12 is an antimicrobial protein secreted by neutrophils during infection.
• S100A12 sequesters transition metals like zinc (Zn²⁺) to modulate human immune responses.
• Metal sequestration by S100A12 is pH-dependent and enhanced by calcium (Ca²⁺).

Purpose of the Study:

• To investigate the pH dependence of human S100A12's zinc sequestration.
• To elucidate the mechanism of calcium-mediated enhancement of metal binding by S100A12.

Main Methods:

• Used Cobalt (Co²⁺) as a surrogate for zinc (Zn²⁺) to study metal binding.
• Investigated pH dependence of Co²⁺ binding to apo-S100A12 and Ca²⁺-S100A12.
• Employed Nuclear Magnetic Resonance (NMR) spectroscopy to analyze structural changes and metal coordination.

Main Results:

• Apo-S100A12 showed strong Co²⁺ binding from pH 7.0 to 10.0, decreasing at pH 5.3.
• Ca²⁺-S100A12 maintained nanomolar Co²⁺ binding affinity up to pH 5.7.
• NMR revealed calcium restricts pH-dependent conformational changes in the EF loop, preserving Asp25's metal-binding site.

Conclusions:

• Calcium binding enhances S100A12's ability to sequester zinc and cobalt ions at lower pH.
• This calcium-induced effect may bolster antimicrobial activity of S100 proteins during neutrophil activation in acidic environments.