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Studies of the biological properties of human beta-defensin 1.

Pazgier M, Prahl A, Hoover DM, Lubkowski J
J Biol Chem 282 1819-29 (2007)
Related entries: 2nlb, 2nlc, 2nld, 2nle, 2nlg, 2nlh, 2nlp, 2nlq, 2nls

Cited: 40 times
EuropePMC logo PMID: 17071614

Abstract

Defensins are small (30-45 amino acid residues) cationic proteins with broad antimicrobial activity against many bacteria and fungi, some enveloped viruses, and other activities such as chemoattraction of a range of different cell types to the sites of inflammation. These proteins represent attractive targets for developing novel antimicrobial agents and modulators of immune responses with therapeutic applicability. In this report, we present the results of functional and structural studies of 26 single-site mutants of human beta-defensin 1 (hBD1). All mutants were assayed for antimicrobial activity against Escherichia coli (ATCC strain 25922) and for chemotactic activity with CCR6-transfected HEK293 cells. To analyze the structural implications of mutagenesis and to verify the correctness of the disulfide connectivity, we used x-ray crystallography to conduct complete structural studies for 10 mutants in which the topology of disulfides was the same as in the native hBD1. Mutations did not induce significant changes of the tertiary structure, suggesting that the observed alterations of biological properties of the mutants were solely associated with changes in the respective side chains. We found that cationic residues located near the C terminus (Arg(29), Lys(31), Lys(33), and Lys(36)) of hBD1 define most of the anti-E. coli in vitro activity of this protein. In turn, nearly all mutations altering the CCR6-mediated chemotaxis are located at one area of the protein, defined by the N-terminal alpha-helical region (Asp(1)... Ser(8)) and a few topologically adjacent residues (Lys(22), Arg(29), and Lys(33)). These experimental results allow for the first time drafting of the CCR6-epitope for a defensin molecule.

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  1. SPARC: Structural properties associated with residue constraints. Neuwald AF, Yang H, Tracy Nixon B. Comput Struct Biotechnol J 20 1702-1715 (2022)


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  1. Topical antimicrobials for burn wound infections. Dai T, Huang YY, Sharma SK, Hashmi JT, Kurup DB, Hamblin MR. Recent Pat Antiinfect Drug Discov 5 124-151 (2010)
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  15. Modification of β-Defensin-2 by Dicarbonyls Methylglyoxal and Glyoxal Inhibits Antibacterial and Chemotactic Function In Vitro. Kiselar JG, Wang X, Dubyak GR, El Sanadi C, Ghosh SK, Lundberg K, Williams WM. PLoS One 10 e0130533 (2015)
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  20. Defensin-related peptide 1 (Defr1) is allelic to Defb8 and chemoattracts immature DC and CD4+ T cells independently of CCR6. Taylor K, Rolfe M, Reynolds N, Kilanowski F, Pathania U, Clarke D, Yang D, Oppenheim J, Samuel K, Howie S, Barran P, Macmillan D, Campopiano D, Dorin J. Eur J Immunol 39 1353-1360 (2009)
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  23. Streptococcus pyogenes infection of tonsil explants is associated with a human β-defensin 1 response from control but not recurrent acute tonsillitis patients. Bell S, Howard A, Wilson JA, Abbot EL, Smith WD, Townes CL, Hirst BH, Hall J. Mol Oral Microbiol 27 160-171 (2012)
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  27. A peptide derived from human bactericidal/permeability-increasing protein (BPI) exerts bactericidal activity against Gram-negative bacterial isolates obtained from clinical cases of bovine mastitis. Chockalingam A, McKinney CE, Rinaldi M, Zarlenga DS, Bannerman DD. Vet Microbiol 125 80-90 (2007)
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