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-Defensin, HD51
* David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095;
Faculty of Veterinary Medicine, Department of Veterinary Sciences, Chair of Physiological Chemistry, Ludwig-Maximilians-University Munich, Munich, Germany; and
Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201
Four of the six human 
-defensins (human neutrophil peptides 1–3 and human -defensin 5; HD5) have a lectin-like ability to bind glycosylated proteins. Using HD5 as a model, we applied surface plasmon resonance techniques to gain insights into this property. HD5 bound natural glycoproteins > neoglycoproteins based on BSA > nonglycosylated BSA >> free sugars. The affinity of HD5 for simple sugars covalently bound to BSA was orders of magnitude greater than its affinity for the same sugars in solution. The affinity of HD5 for protein-bound carbohydrates resulted from multivalent interactions which may also involve noncarbohydrate residues of the proteins. HD5 showed concentration-dependent self-association that began at submicromolar concentrations and proceeded to dimer and tetramer formation at concentrations below 5 µM. The (R9A, R28A) and (R13A, R32A) analogs of HD5 showed greatly reduced self-association as well as minimal binding to BSA and to BSA-affixed sugars. From this and other evidence, we conclude that the extensive binding of HD5 to (neo)glycoproteins results from multivalent nonspecific interactions of individual HD5 molecules with carbohydrate and noncarbohydrate moieties of the target molecule and that the primary binding events are magnified and enhanced by subsequent in situ assembly and oligomerization of HD5. Self-association and multivalent binding may play integral roles in the ability of HD5 to protect against infections caused by viruses and other infectious agents.
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.
1 Supported in part by Grant 5R01AI061482 from the National Institutes of Health (to W.L.) and by the research initiative LMUexcellent.
2 Address correspondence and reprint requests to Dr. Robert I. Lehrer, The David Geffen School of Medicine at UCLA, Center for Health Sciences CHS 37-062, 10833 Le Conte Avenue, Los Angeles, CA 90095-1690. E-mail address: rlehrer{at}mednet.ucla.edu
3 Abbreviations used in this paper: HNP, human neutrophil peptide; BSA-β-D-GlcNAc, a neoglycoprotein containing β-D-N-acetylglucosamine residues covalently bound to BSA; CM, carboxymethylated; FO0.5, the peptide concentration that binds, on average, one-half of the sugar residues on a neoglycoprotein; gD1, glycoprotein D of herpes simplex type 1; HD, human defensin; IC0.5, concentration of an inhibitor that reduces binding of 1 µg/ml HD5 to the binding level shown by 0.5 µg/ml (in this report); m/z, mass divided by charge; MR, molar ratio; RU, response (or resonance) units; SPR, surface plasmon resonance.
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  G. Wei, E. de Leeuw, M. Pazgier, W. Yuan, G. Zou, J. Wang, B. Ericksen, W.-Y. Lu, R. I. Lehrer, and W. Lu Through the Looking Glass, Mechanistic Insights from Enantiomeric Human Defensins J. Biol. Chem., October 16, 2009; 284(42): 29180 - 29192. [Abstract] [Full Text] [PDF]
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