title: The crystal structures of human S100A12 in apo form and in complex with zinc: new insights into S100A12 oligomerisation.
abstract: The functions of the members of the S100 family of EF-hand proteins are modulated by calcium and, in a number of cases, by zinc or copper. One such protein is S100A12, which is implicated in inflammation and host-parasite responses. Previously, we reported the structures of human S100A12 in both low (dimeric) and high (hexameric) calcium forms and, in addition, that of a complex with copper and calcium. Here we report the crystal structures of the metal-free apo form of human S100A12 at 1.77 A resolution and of the zinc complex in two crystal forms (P2(1)2(1)2(1) and F222) to 1.88 A and 1.73 A resolution, respectively. These are the first structures of a zinc-only complex of an S100 protein to be determined. The zinc complex structure shows significant differences from those of both calcium-loaded and apo-S100A12 structures, and comparisons suggest an explanation for the zinc-induced 1500-fold increase in calcium affinity. In addition, the new structures provide insight into the role of zinc-calcium interplay in the transition of S100A12 from a dimer through a tetramer to a hexamer. The role of both zinc and calcium in target binding by S100A12 during host-parasite responses is confirmed by experiments with paramyosin from the tropical parasites Onchocerca volvulus and Brugia malayi.
authors.affiliation: Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5YW, UK. olga@ysbl.york.ac.uk
authors.forename: Olga V
authors.initials: OV
authors.lastname: Moroz
authors.forename: Elena V
authors.initials: EV
authors.lastname: Blagova
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Wilkinson
authors.forename: Keith S
authors.initials: KS
authors.lastname: Wilson
authors.forename: Igor B
authors.initials: IB
authors.lastname: Bronstein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017178:Brugia malayi; D002118:Calcium / Q000378:metabolism; D018360:Crystallography, X-Ray; D015801:Helminth Proteins / Q000737:chemistry; D006790:Host-Parasite Interactions; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017181:Onchocerca volvulus; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D055503:Protein Multimerization; D009418:S100 Proteins / Q000737:chemistry* / Q000378:metabolism; D000067616:S100A12 Protein; D014335:Tropomyosin / Q000737:chemistry; D015032:Zinc / Q000378:metabolism*
chemical_list: D015801:Helminth Proteins; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D014335:Tropomyosin; D015032:Zinc; D002118:Calcium