Abstract

S100A3 is a unique member of the EF-hand superfamily of Ca(2+)-binding proteins. It binds Ca(2+) with poor affinity (K(d) = 4-35 mm) but Zn(2+) with exceptionally high affinity (K(d) = 4 nm). This high affinity for Zn(2+) is attributed to the unusual high Cys content of S100A3. The protein is highly expressed in fast proliferating hair root cells and astrocytoma pointing toward a function in cell cycle control. We determined the crystal structure of the protein at 1.7 A. The high resolution structure revealed a large distortion of the C-terminal canonical EF-hand, which most likely abolishes Ca(2+) binding. The crystal structure of S100A3 allows the prediction of one putative Zn(2+) binding site in the C terminus of each subunit of S100A3 involving Cys and His residues in the coordination of the metal ion. Zn(2+) binding induces a large conformational change in S100A3 perturbing the hydrophobic interface between two S100A3 subunits, as shown by size exclusion chromatography and CD spectroscopy.

Highlights

  • S100A3 is a member of the S100 protein family, which constitutes a large subgroup of the EF-hand family of Ca2ϩ-binding proteins

  • Overall Structure—The crystal structure of human S100A3 was determined by the multiple anomalous dispersion method using xenon and iodide as heavy atom derivatives and was refined at 1.7 Å.1

  • The dimer interface is built by hydrophobic residues located on helices HI/HIVЈ (Leu5, Val9, Ile13, Phe16/Phe72Ј, Val76Ј, Ala80Ј, Cys83Ј, Cys86Ј) and helices HIЈ/HIV (Leu5Ј, Val9Ј, Ile13Ј, Phe16Ј/ Phe72, Val76, Ala80, Cys83, Cys86), further by Tyr27, Tyr27Ј on Loop L1/L1Ј, Trp45, Trp45Ј in the hinge region, and Tyr89, Tyr89Ј, Phe90, and Phe90Ј located on a C-terminal short ␣-helical segment

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Summary

Introduction

S100A3 is a member of the S100 protein family, which constitutes a large subgroup of the EF-hand family of Ca2ϩ-binding proteins. The high resolution structure revealed a large distortion of the C-terminal canonical EF-hand, which most likely abolishes Ca2؉ binding. The crystal structure of S100A3 allows the prediction of one putative Zn2؉ binding site in the C terminus of each subunit of S100A3 involving Cys and His residues in the coordination of the metal ion.

Results
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