The antimicrobial peptide LL-37 belongs to the cathelicidin family and is the first amphipathic α-helical peptide isolated from human. LL-37 is considered to play an important role in the first line of defence against local infection and systemic invasion of pathogens at sites of inflammation and wounds. Understanding its mode of action may assist in the development of antimicrobial agents mimicking those of the human immune system. In vitrostudies revealed that LL-37 is cytotoxic to both bacterial and normal eukaryotic cells. To gain insight into the mechanism of its non-cell-selective cytotoxicity, we synthesized and structurally and functionally characterized LL-37, its N-terminal truncated form FF-33, and their fluorescent derivatives (which retained structure and activity). The results showed several differences, between LL-37 and other native antimicrobial peptides, that may shed light on its in vivoactivities. Most interestingly, LL-37 exists in equilibrium between monomers and oligomers in solution at very low concentrations. Also, it is significantly resistant to proteolytic degradation in solution, and when bound to both zwitterionic (mimicking mammalian membranes) and negatively charged membranes (mimicking bacterial membranes). The results also showed a role for the N-terminus in proteolytic resistance and haemolytic activity, but not in antimicrobial activity. The LL-37 mode of action with negatively charged membranes suggests a detergent-like effect via a ‘carpet-like’ mechanism. However, the ability of LL-37 to oligomerize in zwitterionic membranes might suggest the formation of a transmembrane pore in normal eukaryotic cells. To examine this possibility we used polarized attenuated total reflectance Fourier-transform infrared spectroscopy and found that the peptide is predominantly α-helical and oriented nearly parallel with the surface of zwitterionic-lipid membranes. This result does not support the channel-forming hypothesis, but rather it supports the detergent-like effect.
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August 1999
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Research Article|
July 26 1999
Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity
Ziv OREN;
Ziv OREN
*Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
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Jeffrey C. LERMAN;
Jeffrey C. LERMAN
*Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
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Gudmundur H. GUDMUNDSSON;
Gudmundur H. GUDMUNDSSON
†Microbiology and Tumorbiology Center, Karolinska Institute, S-17177 Stockholm, Sweden
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Birgitta AGERBERTH;
Birgitta AGERBERTH
‡Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-17177 Stockholm, Sweden
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Yechiel SHAI
Yechiel SHAI
1
*Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel
1To whom correspondence should be addressed (e-mail bmshai@weizmann.weizmann.ac.il).
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Publisher: Portland Press Ltd
Received:
January 14 1999
Revision Received:
April 06 1999
Accepted:
May 13 1999
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1999
1999
Biochem J (1999) 341 (3): 501–513.
Article history
Received:
January 14 1999
Revision Received:
April 06 1999
Accepted:
May 13 1999
Citation
Ziv OREN, Jeffrey C. LERMAN, Gudmundur H. GUDMUNDSSON, Birgitta AGERBERTH, Yechiel SHAI; Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity. Biochem J 1 August 1999; 341 (3): 501–513. doi: https://doi.org/10.1042/bj3410501
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