Structure of the human S100A12–copper complex: implications for host-parasite defence

Abstract

S100A12 is a member of the S100 family of EF-hand calcium-modulated proteins. Together with S100A8 and S100A9, it belongs to the calgranulin subfamily, i.e. it is mainly expressed in granulocytes, although there is an increasing body of evidence of expression in keratinocytes and psoriatic lesions. As well as being linked to inflammation, allergy and neuritogenesis, S100A12 is involved in host-parasite response, as are the other two calgranulins. Recent data suggest that the function of the S100-family proteins is modulated not only by calcium, but also by other metals such as zinc and copper. Previously, the structure of human S100A12 in low-calcium and high-calcium structural forms, crystallized in space groups R3 and P2(1), respectively, has been reported. Here, the structure of S100A12 in complex with copper (space group P2(1)2(1)2; unit-cell parameters a = 70.6, b = 119.0, c = 90.2 A) refined at 2.19 A resolution is reported. Comparison of anomalous difference electron-density maps calculated with data collected with radiation of wavelengths 1.37 and 1.65 A shows that each monomer binds a single copper ion. The copper binds at an equivalent site to that at which another S100 protein, S100A7, binds zinc. The results suggest that copper binding may be essential for the functional role of S100A12 and probably the other calgranulins in the early immune response.

The Human Antimicrobial Protein Calgranulin C Participates in Control of Helicobacter pylori Growth and Regulation of Virulence

“…S100A12 is an EF-hand calcium-binding protein that forms an antiparallel noncovalent homodimer (39) and binds calcium, zinc, and copper (14,39,(63)(64)(65). Like other secreted S100 proteins, S100A12 can form higher-order oligomers in the high calcium concentrations outside cells, including tetramers and hexamers (39).…”

Divalent Metal Ion Complexes of S100B in the Absence and Presence of Pentamidine

“…When the Zn 2+ site of S100B [ Fig. 4; Protein Data Bank (PDB) code: 3CR2] was compared to other S100 proteins (using S100B numbering), a structurally conserved Zn 2+ /Cu 2+ binding site, distinct from the two EF-hand Ca 2+ binding sites, was also observed for S100A7 (Zn 2+ : His17/Asp24/His86′/His90′; PDB code: 2PSR) 46 and S100A12 (Cu 2+ : His15/Asp25/His85′/His89′; PDB code: 1ODB) 50,51 (Fig. 8).…”

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

“…As mentioned above, Cu is another important micronutrient for microbes, particularly eukaryotic microbes (2). To date, CP binding to Cu has not been reported, although fluorescence studies suggest that Cu can induce conformational changes in CP (36), and other S100 proteins, including S100B, S100A12, and S100A13, have been shown to bind this metal ion (37)(38)(39)(40), raising the possibility of a role for CP in Cu sequestration.…”