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Statistical analysis of structural characteristics of protein Ca2+-binding sites

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Abstract

To better understand the biological significance of Ca2+, we report a comprehensive statistical analysis of calcium-binding proteins from the Protein Data Bank to identify structural parameters associated with EF-hand and non-EF-hand Ca2+-binding sites. Comparatively, non-EF-hand sites utilize lower coordination numbers (6 ± 2 vs. 7 ± 1), fewer protein ligands (4 ± 2 vs. 6 ± 1), and more water ligands (2 ± 2 vs. 1 ± 0) than EF-hand sites. The orders of ligand preference for non-EF-hand and EF-hand sites, respectively, were H2O (33.1%) > side-chain Asp (24.5%) > main-chain carbonyl (23.9%) > side-chain Glu (10.4%), and side-chain Asp (29.7%) > side-chain Glu (26.6%) > main-chain carbonyl (21.4%) > H2O (13.3%). Less formal negative charge was observed in the non-EF-hand than in the EF-hand binding sites (1 ± 1 vs. 3 ± 1). Additionally, over 20% of non-EF-hand sites had formal charge values of zero due to increased utilization of water and carbonyl oxygen ligands. Moreover, the EF-hand sites presented a narrower range of ligand distances and bond angles than non-EF-hand sites, possibly owing to the highly conserved helix–loop–helix motif. Significant differences between ligand types (carbonyl, side chain, bidentate) demonstrated that angles associated with each type must be classified separately, and the EF-hand side-chain Ca–O–C angles exhibited an unusual bimodal quality consistent with an Asp distribution that differed from the Gaussian model observed for non-EF-hand proteins. The results of this survey more accurately describe differences between EF-hand and non-EF-hand proteins and provide new parameters for the prediction and design of different classes of Ca2+-binding proteins.

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Acknowledgments

We would like to thank Yubin Zhou, Kun Zhao, and other members of J.J.Y.’s laboratory for their critical review of this manuscript and helpful discussions, and Wei Yang from NIH for additional suggestions. This work is supported in part by the following grants: NIH GM081749, NIH GM 62999, and NSF MCB-0092486 to J.J.Y., and DMS-0500951 to G.C.

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Authors and Affiliations

  1. Department of Chemistry, Center for Drug Design and Biotechnology, Georgia State University, Atlanta, GA, 30303, USA

    Michael Kirberger, Wei Yang & Jenny J. Yang

  2. Department of Computer Science, Georgia State University, Atlanta, GA, 30303, USA

    Xue Wang, Hai Deng & Guantao Chen

  3. Department of Mathematics and Statistics, Georgia State University, Atlanta, GA, 30303, USA

    Guantao Chen

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  1. Michael Kirberger
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  2. Xue Wang
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  3. Hai Deng
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  4. Wei Yang
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  5. Guantao Chen
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  6. Jenny J. Yang
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Correspondence to Jenny J. Yang.

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Michael Kirberger, Xue Wang, and Hai Deng contributed equally to this article.

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Kirberger, M., Wang, X., Deng, H. et al. Statistical analysis of structural characteristics of protein Ca2+-binding sites. J Biol Inorg Chem 13, 1169–1181 (2008). https://doi.org/10.1007/s00775-008-0402-7

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