Arginine-lysine positional swap of the LL-37 peptides reveals evolutional advantages of the native sequence and leads to bacterial probes

Xiuqing Wang, José Carlos Bozelli Junior, Biswajit Mishra, Tamara Lushnikova, Richard M. Epand, Guangshun Wang

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Antimicrobial peptides are essential components of the innate immune system of multicellular organisms. Although cationic and hydrophobic amino acids are known determinants of these amphipathic molecules for bacterial killing, it is not clear how lysine-arginine (K-R) positional swaps influence peptide structure and activity. This study addresses this question by investigating two groups of peptides (GF-17 and 17BIPHE2) derived from human cathelicidin LL-37. K-R positional swap showed little effect on minimal inhibitory concentrations of the peptides. However, there are clear differences in bacterial killing kinetics. The membrane permeation patterns vary with peptide and bacterial types, but not changes in fluorescent dyes, salts or pH. In general, the original peptide is more efficient in bacterial killing, but less toxic to human cells, than the K-R swapped peptides, revealing the evolutionary significance of the native sequence for host defense. The characteristic membrane permeation patterns for different bacteria suggest a possible application of these K-R positional-swapped peptides as molecular probes for the type of bacteria. Such differences are related to bacterial membrane compositions: minimal for Gram-positive Staphylococcus aureus with essentially all anionic lipids (cardiolipin and phosphatidylglycerol), but evident for Gram-negative Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli with a mixture of phosphatidylethanolamine and phosphatidylglycerol. Biophysical characterization found similar structures and binding affinities for these peptides in vesicle systems mimicking E. coli and S. aureus. It seems that interfacial arginines of GF-17 are preferred over lysines in bacterial membrane permeation. Our study sheds new light on the design of cationic amphipathic peptides.

Original languageEnglish (US)
Pages (from-to)1350-1361
Number of pages12
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1859
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

arginyllysine
Peptides
Permeation
Membranes
Phosphatidylglycerols
Escherichia coli
Lysine
Arginine
Staphylococcus aureus
Bacteria
CAP18 lipopolysaccharide-binding protein
Molecular Probes
Cardiolipins
Immune system
Poisons
Klebsiella pneumoniae
Fluorescent Dyes
Pseudomonas aeruginosa
Immune System

Keywords

  • Charge swap
  • Host defense peptides
  • Membrane composition
  • Membrane permeation
  • Molecular probe
  • Native sequence

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

Cite this

Arginine-lysine positional swap of the LL-37 peptides reveals evolutional advantages of the native sequence and leads to bacterial probes. / Wang, Xiuqing; Junior, José Carlos Bozelli; Mishra, Biswajit; Lushnikova, Tamara; Epand, Richard M.; Wang, Guangshun.

In: Biochimica et Biophysica Acta - Biomembranes, Vol. 1859, No. 8, 01.08.2017, p. 1350-1361.

Research output: Contribution to journalArticle

Wang, Xiuqing ; Junior, José Carlos Bozelli ; Mishra, Biswajit ; Lushnikova, Tamara ; Epand, Richard M. ; Wang, Guangshun. / Arginine-lysine positional swap of the LL-37 peptides reveals evolutional advantages of the native sequence and leads to bacterial probes. In: Biochimica et Biophysica Acta - Biomembranes. 2017 ; Vol. 1859, No. 8. pp. 1350-1361.
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AU - Epand, Richard M.

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AB - Antimicrobial peptides are essential components of the innate immune system of multicellular organisms. Although cationic and hydrophobic amino acids are known determinants of these amphipathic molecules for bacterial killing, it is not clear how lysine-arginine (K-R) positional swaps influence peptide structure and activity. This study addresses this question by investigating two groups of peptides (GF-17 and 17BIPHE2) derived from human cathelicidin LL-37. K-R positional swap showed little effect on minimal inhibitory concentrations of the peptides. However, there are clear differences in bacterial killing kinetics. The membrane permeation patterns vary with peptide and bacterial types, but not changes in fluorescent dyes, salts or pH. In general, the original peptide is more efficient in bacterial killing, but less toxic to human cells, than the K-R swapped peptides, revealing the evolutionary significance of the native sequence for host defense. The characteristic membrane permeation patterns for different bacteria suggest a possible application of these K-R positional-swapped peptides as molecular probes for the type of bacteria. Such differences are related to bacterial membrane compositions: minimal for Gram-positive Staphylococcus aureus with essentially all anionic lipids (cardiolipin and phosphatidylglycerol), but evident for Gram-negative Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli with a mixture of phosphatidylethanolamine and phosphatidylglycerol. Biophysical characterization found similar structures and binding affinities for these peptides in vesicle systems mimicking E. coli and S. aureus. It seems that interfacial arginines of GF-17 are preferred over lysines in bacterial membrane permeation. Our study sheds new light on the design of cationic amphipathic peptides.

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