Human Defensins: Synthesis and Structural Properties

Abstract

Defensins are small, beta-sheet-rich, cationic peptides found in many organisms. All defensins have amphiphilic properties, which are central for antimicrobial activities of the proteins. The human genome encodes many defensin-line molecules, of which 10 have been characterized. Molecules of all known human defensins are stabilized by three intramolecular disulfide bonds arranged in a conserved pattern. To date, studies of human defensins indicate that these proteins are involved in various biological processes associated primarily with defensive and regulatory responses to infections by pathological agents. A comprehensive understanding of the multiple roles played by defensins within the immune system is greatly increased by reviewing the results of detailed structural studies. Emerging structural data, derived by the X-ray crystallography and the NMR spectroscopy in solution combined with functional studies; allow a rational understanding of the different activities of defensins and the mechanisms controlling these activities. Due to their well-established antimicrobial properties, defensins are also being investigated for their potential as therapeutics agents. Recently, increased effort has been focused on studies of the immunoregulatory properties of defensins, associated with their ability to bind and activate the G(i)-protein-coupled seven-transmembrane receptors. Comprehensive studies of defensins require development of simple, efficient, and inexpensive methods to generate these proteins and their derivatives in correctly folded form. This review highlights the current status of the sample generation methods, structural studies, and the structure-function relationships for human defensins.

Comparative Analysis of the Antimicrobial Activities of Plant Defensin-Like and Ultrashort Peptides against Food-Spoiling Bacteria

“…Defensins generally range from 45 to 54 amino acids, and although the peptides differ greatly at the amino acid sequence level, they possess many conserved structural and biochemical features, such as twisted antiparallel beta-sheets, a short amphipathic ␣-helix, conserved cysteine residues, an overall positive net charge, and a net negative hydrophobicity score (28). Based on the pattern of intramolecular disulfide bonds formed by the cysteine residues, defensins are classified as alpha-or beta-defensins (29).…”

Antimicrobial and antiviral effects of human defensins: pathogenetic value and prospective application to medicinal therapy

“…В организме человека присутствуют в качестве действующих агентов два вида -α-и β-дефенсины. В настоящее время у человека идентифицировано шесть видов α-дефенсинов и свыше 30 β-дефенсинов [154]. Основным депо и источником секреции четы-рех α-дефенсинов (HNP-1, HNP-2, HNP-3, HNP-4) являются нейтрофилы, поэтому им присвоена аб-бревиатура HNP (human neutrophils peptides) и соот-ветствующие порядковые номера.…”

“…Именно такими участками АМП связываются с отри-цательно заряженными липополисахаридами (ЛПС) внешней мембраны грамотрицательных бактерий [137]. Возникающие при этом структурные изме-нения в ЛПС-слое образуют так называемый «вер-тикальный саморегулирующийся канал», облегча-ющий дефенcину проникновение к плазматической мембране патогена [154]. Полагают, что таким обра-зом АМП создают трещины в ЛПС-слое (рис.…”

“…Однако потеря спе цифических остатков аргинина является кри-тической для привязки НD-5 к аденовирусу типа 5 и ВПЧ-16 и эта функция не является чисто заряд-за-висимой, так как замена аминокислотного остатка аргинина на лизин не сохраняет противовирусную активность. Кроме того, способность дефенcина HD-5 самостоятельно привязываться критична для степени противовирусной активности в отношении аденовируса типа 5 и вируса ВПЧ-16, а также для привязки белка gp120 ВИЧ-1 [83,154]. Эти особен-ности функций дефенсинов были выявлены посред-ством мутаций, которые нарушали активность де-фенсинов.…”

ADP-ribosylation of human defensin HNP-1 results in the replacement of the modified arginine with the noncoded amino acid ornithine

“…Effects of sequence and structure on the biological activity of the ␣-defensins have been studied by several investigators (19). After ADP-ribosylation by ART1, HNP-1 had reduced antimicrobial and cytotoxic activities but maintained its ability to recruit T lymphocytes and release IL-8 from A549 cells (17).…”