title: Thermodynamic instability of viral proteins is a pathogen-associated molecular pattern targeted by human defensins.
abstract: Human defensins are innate immune defense peptides with a remarkably broad repertoire of anti-pathogen activities. In addition to modulating immune response, inflammation, and angiogenesis, disintegrating bacterial membranes, and inactivating bacterial toxins, defensins are known to intercept various viruses at different stages of their life cycles, while remaining relatively benign towards human cells and proteins. Recently we have found that human defensins inactivate proteinaceous bacterial toxins by taking advantage of their low thermodynamic stability and acting as natural "anti-chaperones", i.e. destabilizing the native conformation of the toxins. In the present study we tested various proteins produced by several viruses (HIV-1, PFV, and TEV) and found them to be susceptible to destabilizing effects of human α-defensins HNP-1 and HD-5 and the synthetic θ-defensin RC-101, but not β-defensins hBD-1 and hBD-2 or structurally related plant-derived peptides. Defensin-induced unfolding promoted exposure of hydrophobic groups otherwise confined to the core of the viral proteins. This resulted in precipitation, an enhanced susceptibility to proteolytic cleavage, and a loss of viral protein activities. We propose, that defensins recognize and target a common and essential physico-chemical property shared by many bacterial toxins and viral proteins - the intrinsically low thermodynamic protein stability.
authors: Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
authors: Elena
authors: E
authors: Kudryashova
authors: Center for Retroviral Research, The Ohio State University, Columbus, OH 43210, USA.|College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors: Pratibha C
authors: PC
authors: Koneru
authors: Center for Retroviral Research, The Ohio State University, Columbus, OH 43210, USA.|College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors: Mamuka
authors: M
authors: Kvaratskhelia
authors: Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, 75123 Uppsala, Sweden.
authors: Adam A
authors: AA
authors: Strömstedt
authors: Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors: Wuyuan
authors: W
authors: Lu
authors: Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.|Public Health Preparedness for Infectious Diseases Program, The Ohio State University, Columbus, OH 43210, USA.
authors: Dmitri S
authors: DS
authors: Kudryashov
mesh_terms: D011232:Chemical Precipitation; D015497:HIV-1 / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D017800:Potyvirus / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability; D058767:Protein Unfolding; D059748:Proteolysis; D053150:Simian foamy virus / Q000737:chemistry; D013816:Thermodynamics; D014764:Viral Proteins / Q000737:chemistry*; D023084:alpha-Defensins / Q000138:chemical synthesis / Q000737:chemistry*; D023083:beta-Defensins / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: C500225:DEFA5 protein, human; C406407:DEFB1 protein, human; C106641:DEFB4A protein, human; D010455:Peptides; C450143:RC 101; D014764:Viral Proteins; D023084:alpha-Defensins; D023083:beta-Defensins; C406413:human neutrophil peptide 1