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J. Biol. Chem., Vol. 281, Issue 38, 28068-28078, September 22, 2006

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Structural and Functional Characterization of the Conserved Salt Bridge in Mammalian Paneth Cell -Defensins

SOLUTION STRUCTURES OF MOUSE CRYPTDIN-4 AND (E15D)-CRYPTDIN-4^*

K. Johan Rosengren¹, Norelle L. Daly², Liselotte M. Fornander, Linda M. H. Jönsson, Yoshinori Shirafuji^¶, Xiaoqing Qu^¶, Hans J. Vogel^||3, Andre J. Ouellette^¶, and David J. Craik⁴

From the Department of Chemistry and Biomedical Sciences, University of Kalmar, SE-391 82 Kalmar, Sweden, the Institute for Molecular Bioscience and Australian Research Council Special Research Centre for Functional and Applied Genomics, University of Queensland, Brisbane, Queensland 4072, Australia, the ^¶Departments of Pathology & Laboratory Medicine and Microbiology & Molecular Genetics, School of Medicine, University of California, Irvine, California 92697-4800, and the ^||Structural Biology Research Group, Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada

-Defensins are mediators of mammalian innate immunity, and knowledge of their structure-function relationships is essential for understanding their mechanisms of action. We report here the NMR solution structures of the mouse Paneth cell -defensin cryptdin-4 (Crp4) and a mutant (E15D)-Crp4 peptide, in which a conserved Glu¹⁵ residue was replaced by Asp. Structural analysis of the two peptides confirms the involvement of this Glu in a conserved salt bridge that is removed in the mutant because of the shortened side chain. Despite disruption of this structural feature, the peptide variant retains a well defined native fold because of a rearrangement of side chains, which result in compensating favorable interactions. Furthermore, salt bridge-deficient Crp4 mutants were tested for bactericidal effects and resistance to proteolytic degradation, and all of the variants had similar bactericidal activities and stability to proteolysis. These findings support the conclusion that the function of the conserved salt bridge in Crp4 is not linked to bactericidal activity or proteolytic stability of the mature peptide.

Received for publication, May 24, 2006 , and in revised form, July 14, 2006.

^* This work was supported in part by funds from the University of Kalmar (to K. J. R.), funds from the Australian Research Council (to D. J. C.), and National Institutes of Health Grant DK44632 and support from the Human Frontiers Science Program and the United States-Israel Binational Science Foundation (to A. J. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains five supplementary figures.

The atomic coordinates and structure factors (codes 2GW9 and 2GWP) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

² National Health and Medical Research Council, Australia industry fellow.

³ Recipient of a Scientist Award from the Alberta Heritage Foundation for Medical Research.

⁴ An Australian Research Council Professorial Fellow.

¹ To whom correspondence should be addressed. Tel.: 46-480-446152; Fax: 46-480-446262; E-mail: johan.rosengren{at}hik.se.

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