Abstract
The S100A3 homotetramer assembles upon citrullination of a specific symmetric Arg51 pair on its homodimer interface in human hair cuticular cells. Each S100A3 subunit contains two EF-hand-type Ca2+-binding motifs and one (Cys)3His-type Zn2+-binding site in the C-terminus. The C-terminal coiled domain is cross-linked to the presumed docking surface of the dimeric S100A3 via a disulfide bridge. The aim of this study was to determine the structural and functional role of the C-terminal Zn2+-binding domain, which is unique to S100A3, in homotetramer assembly. The binding of either Ca2+ or Zn2+ reduced the α-helix content of S100A3 and modulated its affinity for the other cation. The binding of a single Zn2+ accelerated the Ca2+-dependent tetramerization of S100A3 while inducing an extensive unfolding of helix IV. The Ca2+ and Zn2+ binding affinities of S100A3 were enhanced when the other cation bound in concert with the tetramerization of S100A3. Small angle scattering analyses revealed that the overall structure of the S100A3 tetramer bound both Ca2+ and Zn2+ had a similar molecular shape to the Ca2+-bound form in solution. The binding states of the Ca2+ or Zn2+ to each S100A3 subunit within a homotetramer appear to be propagated by sensing the repositioning of helix III and the rearrangement of the C-terminal tail domain. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.
Published Version
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