Journal article
Criterion for amino acid composition of defensins and antimicrobial peptides based on geometry of membrane destabilization
Journal of the American Chemical Society, Vol.133(17), pp.6720-6727
05/04/2011
DOI: 10.1021/ja200079a
PMCID: PMC3090259
PMID: 21473577
Abstract
Defensins comprise a potent class of membrane disruptive antimicrobial peptides (AMPs) with well-characterized broad spectrum and selective microbicidal effects. By using high-resolution synchrotron small angle x-ray scattering to investigate interactions between heterogeneous membranes and members of the defensin subfamilies, α-defensins (Crp-4), β-defensins (HBD-2, HBD-3), and θ-defensins (RTD-1, BTD-7), we show how these peptides all permeabilize model bacterial membranes but not model eukaryotic membranes: defensins selectively generate saddle-splay (‘negative Gaussian’) membrane curvature in model membranes rich in negative curvature lipids such as those with phosphoethanolamine (PE) headgroups. These results are shown to be consistent with vesicle leakage assays. A mechanism of action based on saddle-splay membrane curvature generation is broadly enabling, since it is a necessary condition for processes such as pore formation, blebbing, budding, vesicularization, all of which destabilize the barrier function of cell membranes. Importantly, saddle-splay membrane curvature generation places constraints on the amino acid composition of membrane disruptive peptides. For example, we show that the requirement for generating saddle-splay curvature implies that a decrease in arginine content in an AMP can be offset by an increase in both lysine and hydrophobic content. This ‘design rule’ is consistent with the amino acid compositions of 1,080 known cationic AMPs.
Details
- Title: Subtitle
- Criterion for amino acid composition of defensins and antimicrobial peptides based on geometry of membrane destabilization
- Creators
- Nathan W Schmidt - Department of Physics, University of Illinois, Urbana-Champaign, IL 61801Abhijit Mishra - Department of Bioengineering, University of California, Los Angeles, CA 90095Ghee Hwee Lai - Department of Physics, University of Illinois, Urbana-Champaign, IL 61801Matthew Davis - Department of Materials Science, University of Illinois, Urbana-Champaign, IL 61801Lori K Sanders - Department of Materials Science, University of Illinois, Urbana-Champaign, IL 61801Dat Tran - Department of Pathology & Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089-9601Angie Garcia - Department of Pathology & Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089-9601Kenneth P Tai - Department of Pathology & Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089-9601Paul B McCray - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242André J Ouellette - Department of Pathology & Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089-9601Michael E Selsted - Department of Pathology & Laboratory Medicine, USC Norris Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089-9601Gerard C. L Wong - Department of Physics, University of Illinois, Urbana-Champaign, IL 61801
- Resource Type
- Journal article
- Publication Details
- Journal of the American Chemical Society, Vol.133(17), pp.6720-6727
- DOI
- 10.1021/ja200079a
- PMID
- 21473577
- PMCID
- PMC3090259
- NLM abbreviation
- J Am Chem Soc
- ISSN
- 0002-7863
- eISSN
- 1520-5126
- Grant note
- U01 AI082192-01 || AI / National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID R01 AI058129-05 || AI / National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID R01 DE015517-04 || DE / National Institute of Dental and Craniofacial Research : NIDCR R01 DK044632-19 || DK / National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK R37 AI022931-25 || AI / National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID P01 HL091842-04 || HL / National Heart, Lung, and Blood Institute : NHLBI P50 HL061234-10 || HL / National Heart, Lung, and Blood Institute : NHLBI R01 AI059346-05 || AI / National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
- Language
- English
- Date published
- 05/04/2011
- Academic Unit
- Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9984093361802771
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