Tool Developments for Structure-Function Studies of Host Defense Peptides

Wang, Guangshun

doi:10.2174/092986607779117182

Cited by 26 publications

(13 citation statements)

References 145 publications

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“…The interest in LL-37 has been growing worldwide as evidenced by an exponential increase in related literature in PubMed (38). To improve our understanding of the structure and function of this important host defense cathelicidin, my laboratory has been interested in the structural determination of LL-37 and its complexes with other molecules.…”

Section: Discussionmentioning

confidence: 99%

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Structures of Human Host Defense Cathelicidin LL-37 and Its Smallest Antimicrobial Peptide KR-12 in Lipid Micelles

Wang

2008

Journal of Biological Chemistry

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391

534

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As a key component of the innate immunity system, human cathelicidin LL-37 plays an essential role in protecting humans against infectious diseases. To elucidate the structural basis for its targeting bacterial membrane, we have determined the high quality structure of 13 C, 15 N-labeled LL-37 by three-dimensional triple-resonance NMR spectroscopy, because two-dimensional 1 H NMR did not provide sufficient spectral resolution. The structure of LL-37 in SDS micelles is composed of a curved amphipathic helix-bend-helix motif spanning residues 2-31 followed by a disordered C-terminal tail. The helical bend is located between residues Gly-14 and Glu-16. Similar chemical shifts and 15 N nuclear Overhauser effect (NOE) patterns of the peptide in complex with dioctanoylphosphatidylglycerol (D8PG) micelles indicate a similar structure. The aromatic rings of Phe-5, Phe-6, Phe-17, and Phe-27 of LL-37, as well as arginines, showed intermolecular NOE cross-peaks with D8PG, providing direct evidence for the association of the entire amphipathic helix with anionic lipid micelles. The structure of LL-37 serves as a model for understanding the structure and function relationship of homologous primate cathelicidins. Using synthetic peptides, we also identified the smallest antibacterial peptide KR-12 corresponding to residues 18 -29 of LL-37. Importantly, KR-12 displayed a selective toxic effect on bacteria but not human cells. NMR structural analysis revealed a short three-turn amphipathic helix rich in positively charged side chains, allowing for effective competition for anionic phosphatidylglycerols in bacterial membranes. KR-12 may be a useful peptide template for developing novel antimicrobial agents of therapeutic use.The growing drug resistance problem of pathogenic bacteria with traditional antibiotics calls for an urgent search for a new generation of antimicrobial agents. Antimicrobial peptides are ancient and potent weapons of the innate immunity of all life forms (1-4). The recently updated Antimicrobial Peptide Data base collects more than 1228 such peptides (5). In mammals, defensins and cathelicidins are the two major families of antimicrobial peptides. While several cathelicidins were found in animals such as sheep, cow, and pig, only one cathelicidin was identified in humans (6). The precursor proteins of the cathelicidin family share a highly conserved N-terminal "cathelin" domain, but have a highly variable C-terminal antimicrobial region. Upon bacterial insult, human cathelicidin LL-37 (named based on the first two amino acids in the sequence followed by the number of residues in the peptide) is released by proteases from its precursor hCAP-18 (i.e. human cationic antimicrobial protein, ϳ18 kDa). The importance of this host defense peptide to human health is now firmly established. Patients lacking this molecule are more susceptible to infections (7). While cathelicidin knock-out mice are more readily infected (8), expression of additional cathelicidins protects the animals from infection (9). LL-37 also ass...

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Section: Discussionmentioning

confidence: 99%

“…2B) contains the primary antimicrobial region of LL-37 (37)(38)(39)(40). Using NMR, we previously mapped a core antimicrobial and anticancer region to residues 17-29 (FK-13) of LL-37 (31).…”

Section: Solution Structure Of Human Ll-37 In Complex With Sds Micellmentioning

confidence: 99%

Structures of Human Host Defense Cathelicidin LL-37 and Its Smallest Antimicrobial Peptide KR-12 in Lipid Micelles

Wang

2008

Journal of Biological Chemistry

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391

534

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“…LL-37 is found at lower concentrations in the airways of individuals with cystic fibrosis who are more prone to infection (5). In vitro, this human cathelicidin peptide shows antimicrobial activity against gram-positive bacteria, gram-negative bacteria, viruses, and fungi (30,34). A variety of approaches were applied in identifying fragments of LL-37 that retain antimicrobial activity (4,13,18,25,26).…”

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confidence: 99%

Lipid Segregation Explains Selective Toxicity of a Series of Fragments Derived from the Human Cathelicidin LL-37

Epand

Wang²,

Berno

et al. 2009

Antimicrob Agents Chemother

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The only human cathelicidin, the 37-residue peptide LL-37, exhibits antimicrobial activity against both gram-positive and gram-negative bacteria. We studied the ability of several fragments of LL-37, exhibiting different antimicrobial activities, to interact with membranes whose compositions mimic the cytoplasmic membranes of gram-positive or of gram-negative bacteria. These fragments are as follows: KR-12, the smallest active segment of LL-37, with the sequence KRIVQRIKDFLR, which exhibits antimicrobial activity only against gram-negative bacteria; a slightly smaller peptide, RI-10, missing the two cationic residues at the N and C termini of KR-12, which has been shown not to have any antimicrobial activity; a longer peptide, GF-17, which shows antimicrobial activity against gram-positive as well as gram-negative bacteria; and GF-17D3, with 3 D-amino-acid residues, which is also selective only for gram-negative bacteria. Those fragments with the capacity to cluster anionic lipids away from zwitterionic lipids in a membrane exhibit selective toxicity toward bacteria containing zwitterionic as well as anionic lipids in their cytoplasmic membranes but not toward bacteria with only anionic lipids. This finding allows for the prediction of the bacterial-species selectivity of certain agents and paves the way for designing new antimicrobials targeted specifically toward gram-negative bacteria.

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“…Furthermore, several laboratories have identified active fragments within LL-37 by synthesizing peptides corresponding to different regions (4,20,21,29). Using nuclear magnetic resonance spectroscopy, we previously identified a minimally antimicrobial and anticancer region corresponding to residues 17 to 29 (FK-13 in Table 1) (13).…”

mentioning

confidence: 99%

Anti-Human Immunodeficiency Virus Type 1 Activities of Antimicrobial Peptides Derived from Human and Bovine Cathelicidins

Wang

Watson

Buckheit

2008

Antimicrob Agents Chemother

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101

114

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From among 15 human cathelicidin LL-37-derived peptides, FK-13 was identified as the smallest peptide active against human immunodeficiency virus (HIV) and GI-20 had the highest therapeutic index, which was twice that of LL-37. BMAP-18, which is derived from bovine cathelicidin BMAP-27, possessed a therapeutic index similar to that of GI-20. Peptide sequence order, helical structures, and aromatic residues are important in HIV inhibition.

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Tool Developments for Structure-Function Studies of Host Defense Peptides

Cited by 26 publications

References 145 publications

Structures of Human Host Defense Cathelicidin LL-37 and Its Smallest Antimicrobial Peptide KR-12 in Lipid Micelles

Structures of Human Host Defense Cathelicidin LL-37 and Its Smallest Antimicrobial Peptide KR-12 in Lipid Micelles

Lipid Segregation Explains Selective Toxicity of a Series of Fragments Derived from the Human Cathelicidin LL-37

Anti-Human Immunodeficiency Virus Type 1 Activities of Antimicrobial Peptides Derived from Human and Bovine Cathelicidins

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