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Published online before print November 6, 2006, 10.1110/ps.062336606
Protein Science (2006), 15:2749-2760. Published by Cold Spring Harbor Laboratory Press. Copyright © 2006 The Protein Society
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Crystal structures of human {alpha}-defensins HNP4, HD5, and HD6

Agnieszka Szyk1, Zhibin Wu2, Kenneth Tucker3, De Yang4, Wuyuan Lu2, and Jacek Lubkowski1

1 Macromolecular Assembly Structure and Cell Signaling Section, National Cancer Institute, Frederick, Maryland 21702, USA
2 Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, USA
3 Opportunistic Infection Laboratory, DCTD/DTP, SAIC-Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702, USA
4 Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, Maryland 21702, USA

(RECEIVED May 8, 2006; FINAL REVISION July 18, 2006; ACCEPTED July 18, 2006)

Six {alpha}-defensins have been found in humans. These small arginine-rich peptides play important roles in various processes related to host defense, being the effectors and regulators of innate immunity as well as enhancers of adoptive immune responses. Four defensins, called neutrophil peptides 1 through 4, are stored primarily in polymorphonuclear leukocytes. Major sites of expression of defensins 5 and 6 are Paneth cells of human small intestine. So far, only one structure of human {alpha}-defensin (HNP3) has been reported, and the properties of the intestine defensins 5 and 6 are particularly poorly understood. In this report, we present the high-resolution X-ray structures of three human defensins, 4 through 6, supplemented with studies of their antimicrobial and chemotactic properties. Despite only modest amino acid sequence identity, all three defensins share their tertiary structures with other known {alpha}- and beta-defensins. Like HNP3 but in contrast to murine or rabbit {alpha}-defensins, human defensins 4–6 form characteristic dimers. Whereas antimicrobial and chemotactic activity of HNP4 is somewhat comparable to that of other human neutrophil defensins, neither of the intestinal defensins appears to be chemotactic, and for HD6 also an antimicrobial activity has yet to be observed. The unusual biological inactivity of HD6 may be associated with its structural properties, somewhat standing out when compared with other human {alpha}-defensins. The strongest cationic properties and unique distribution of charged residues on the molecular surface of HD5 may be associated with its highest bactericidal activity among human {alpha}-defensins.

Keywords: human {alpha}-defensins; crystal structures; antimicrobial peptides; chemotaxis


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