title: Trp-26 imparts functional versatility to human alpha-defensin HNP1.
abstract: We performed a comprehensive alanine scan of human alpha-defensin HNP1 and tested the ability of the resulting analogs to kill Staphylococcus aureus, inhibit anthrax lethal factor, and bind human immunodeficiency virus-1 gp120. By far, the most deleterious mutation for all of these functions was W26A. The activities lost by W26A-HNP1 were restored progressively by replacing W26 with non-coded, straight-chain aliphatic amino acids of increasing chain length. The hydrophobicity of residue 26 also correlated with the ability of the analogs to bind immobilized wild type HNP1 and to undergo further self-association. Thus, the hydrophobicity of residue 26 is not only a key determinant of the direct interactions of HNP1 with target molecules, but it also governs the ability of this peptide to form dimers and more complex quaternary structures at micromolar concentrations. Although all defensin peptides are cationic, their amphipathicity is at least as important as their positive charge in enabling them to participate in innate host defense.
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.forename: Marzena
authors.initials: M
authors.lastname: Pazgier
authors.forename: Erik
authors.initials: E
authors.lastname: de Leeuw
authors.forename: Mohsen
authors.initials: M
authors.lastname: Rajabi
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Guozhang
authors.initials: G
authors.lastname: Zou
authors.forename: Grace
authors.initials: G
authors.lastname: Jung
authors.forename: Weirong
authors.initials: W
authors.lastname: Yuan
authors.forename: Wei-Yue
authors.initials: WY
authors.lastname: Lu
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lehrer
authors.forename: Wuyuan
authors.initials: W
authors.lastname: Lu
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007113:Immunity, Innate / Q000502:physiology; D020125:Mutation, Missense; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013211:Staphylococcus aureus / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D023084:alpha-Defensins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D015699:HIV Envelope Protein gp120; D023084:alpha-Defensins; C030325:anthrax toxin; C514793:gp120 protein, Human immunodeficiency virus 1; C406413:human neutrophil peptide 1; D014364:Tryptophan