S100 calcium-binding protein A12 (S100A12), also known as calgranulin C, is a 12 kDa EF-hand calcium-binding protein encoded by the S100A12 gene in humans . First identified in 1995, it is primarily expressed in neutrophils and monocytes/macrophages, with extracellular roles in innate immunity and intracellular regulatory functions . S100A12 acts as a damage-associated molecular pattern (DAMP) molecule, linking cellular stress to inflammatory responses via receptors such as TLR4 and RAGE .
Calcium-dependent signaling: Modulates cytoskeletal dynamics and neutrophil migration .
Immune activation:
Antimicrobial activity: Sequesters zinc and copper, limiting pathogen virulence .
TLR4 activation: S100A12 binds TLR4 on monocytes, inducing chemotaxis and proinflammatory gene expression (e.g., CXCL10, CCL3) .
RAGE interaction: Drives oxidative stress and vascular dysfunction in chronic kidney disease .
S100 Calcium Binding Protein A12 (S100A12), also known as calgranulin C, is a member of the S100 family of EF-hand calcium-binding proteins. This family comprises at least 21 low molecular weight proteins characterized by the presence of two calcium-binding EF-hand motifs . S100A12 is predominantly expressed in neutrophils and plays a significant role in the inflammatory response .
S100A12 is organized as a symmetric, anti-parallel homodimer, with each monomer containing a C-terminal EF-hand motif and an N-terminal pseudo EF-hand motif . The C-terminal EF-hand motif has a high affinity for calcium, while the N-terminal pseudo EF-hand motif binds calcium with lower affinity . In addition to calcium, S100A12 also binds zinc and copper, which are essential for its oligomerization and function .
S100A12 is involved in various physiological and pathophysiological processes, including host defense, inflammation, and cell signaling . It is secreted and upregulated during acute and chronic infections, functioning as a proinflammatory alarmin . Upon calcium-dependent activation, S100A12 interacts with target proteins to regulate cellular functions . Extracellularly, it exists as homodimers and hexamers, exhibiting cytokine-like characteristics .
Elevated serum levels of S100A12 are found in patients with various inflammatory, neurodegenerative, metabolic, and neoplastic disorders . It interacts with the Receptor for Advanced Glycation End products (RAGE) and its soluble form (sRAGE), playing a central role in the pathogenesis of these conditions . S100A12 has potential as a sensitive and specific diagnostic marker for localized inflammatory processes .
Research has shown that both calcium and zinc are essential for the oligomerization and target recognition of S100A12 . This protein has been implicated in the regulation of zinc metabolism and the cross-talk between zinc and calcium in cell signaling . Human recombinant S100A12 is used in various research applications to study its role in inflammation and other diseases.