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A strong 13C chemical shift signature provides the coordination mode of histidines in zinc-binding proteins

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Abstract

Zinc is the second most abundant metal ion incorporated in proteins, and is in many cases a crucial component of protein three-dimensional structures. Zinc ions are frequently coordinated by cysteine and histidine residues. Whereas cysteines bind to zinc via their unique Sγ atom, histidines can coordinate zinc with two different coordination modes, either Nδ1 or Nε2 is coordinating the zinc ion. The determination of this coordination mode is crucial for the accurate structure determination of a histidine-containing zinc-binding site by NMR. NMR chemical shifts contain a vast amount of information on local electronic and structural environments and surprisingly their utilization for the determination of the coordination mode of zinc-ligated histidines has been limited so far to 15N nuclei. In the present report, we observed that the 13C chemical shifts of aromatic carbons in zinc-ligated histidines represent a reliable signature of their coordination mode. Using a statistical analysis of 13C chemical shifts, we show that 13Cδ2 chemical shift is sensitive to the histidine coordination mode and that the chemical shift difference δ{13Cε1} − δ{13Cδ2} provides a reference-independent marker of this coordination mode. The present approach allows the direct determination of the coordination mode of zinc-ligated histidines even with non-isotopically enriched protein samples and without any prior structural information.

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Acknowledgments

We are grateful to Thomas Aeschbacher, Fionna Loughlin and Lawrence P. McIntosh for helpful discussions. Research in the Allain laboratory is supported by the Swiss National Science Foundation (Nr 31003E−131031) and the SNF-NCCR structural biology. P.B. was supported by the Postdoctoral ETH Fellowship Program. Author contributions: P.B. designed the project and analyzed the data; P.B., M.S. and F.H.-T.A. wrote the manuscript; all authors discussed the results and approved the manuscript.

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  1. Institute of Molecular Biology and Biophysics, ETH Zurich, Schafmattstrasse 20, 8093, Zurich, Switzerland

    Pierre Barraud, Mario Schubert & Frédéric H.-T. Allain

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  1. Pierre Barraud
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  2. Mario Schubert
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  3. Frédéric H.-T. Allain
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Correspondence to Pierre Barraud or Frédéric H.-T. Allain.

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Barraud, P., Schubert, M. & Allain, F.HT. A strong 13C chemical shift signature provides the coordination mode of histidines in zinc-binding proteins. J Biomol NMR 53, 93–101 (2012). https://doi.org/10.1007/s10858-012-9625-6

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