Structural characterization of S100A15 reveals a novel zinc coordination site among S100 proteins and altered surface chemistry with functional implications for receptor binding
Date
2012-07-02
Authors
Murray, Jill I
Tonkin, Michelle L
Whiting, Amanda Lee
Peng, Fangni
Farnell, Benjamin
Cullen, Jay T
Hof, Fraser
Boulanger, Martin J
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
Abstract
Background: S100 proteins are a family of small, EF-hand containing calcium-binding signaling proteins that are
implicated in many cancers. While the majority of human S100 proteins share 25-65% sequence similarity, S100A7
and its recently identified paralog, S100A15, display 93% sequence identity. Intriguingly, however, S100A7 and
S100A15 serve distinct roles in inflammatory skin disease; S100A7 signals through the receptor for advanced
glycation products (RAGE) in a zinc-dependent manner, while S100A15 signals through a yet unidentified G-protein
coupled receptor in a zinc-independent manner. Of the seven divergent residues that differentiate S100A7 and
S100A15, four cluster in a zinc-binding region and the remaining three localize to a predicted receptor-binding
surface.
Results: To investigate the structural and functional consequences of these divergent clusters, we report the X-ray
crystal structures of S100A15 and S100A7D24G, a hybrid variant where the zinc ligand Asp24 of S100A7 has been
substituted with the glycine of S100A15, to 1.7 Å and 1.6 Å resolution, respectively. Remarkably, despite
replacement of the Asp ligand, zinc binding is retained at the S100A15 dimer interface with distorted tetrahedral
geometry and a chloride ion serving as an exogenous fourth ligand. Zinc binding was confirmed using anomalous
difference maps and solution binding studies that revealed similar affinities of zinc for S100A15 and S100A7.
Additionally, the predicted receptor-binding surface on S100A7 is substantially more basic in S100A15 without
incurring structural rearrangement.
Conclusions: Here we demonstrate that S100A15 retains the ability to coordinate zinc through incorporation of an
exogenous ligand resulting in a unique zinc-binding site among S100 proteins. The altered surface chemistry
between S100A7 and S100A15 that localizes to the predicted receptor binding site is likely responsible for the
differential recognition of distinct protein targets. Collectively, these data provide novel insight into the structural
and functional consequences of the divergent surfaces between S100A7 and S100A15 that may be exploited for
targeted therapies.
Description
BioMed Central
Keywords
S100A15, S100A7, Zinc-binding, EF hand, X-ray crystallography
Citation
Murray et al.: Structural characterization of S100A15 reveals a novel zinc coordination site among S100 proteins and altered surface chemistry with functional implications for receptor binding. BMC Structural Biology 2012 12:16.