High-quality 3D structures shine light on antibacterial, anti-biofilm and antiviral activities of human cathelicidin LL-37 and its fragments.
Host defense antimicrobial peptides are key components of human innate immunity that plays an indispensible role in human health. While there are multiple copies of cathelicidin genes in horses, cattle, pigs, and sheep, only one cathelicidin gene is found in humans. Interestingly, this single cathelicidin gene can be processed into different forms of antimicrobial peptides. LL-37, the most commonly studied form, is not only antimicrobial but also possesses other functional roles such as chemotaxis, apoptosis, wound healing, immune modulation, and cancer metastasis. This article reviews recent advances made in structural and biophysical studies of human LL-37 and its fragments, which serve as a basis to understand their antibacterial, anti-biofilm and antiviral activities. High-quality structures were made possible by using improved 2D NMR methods for peptide fragments and 3D NMR spectroscopy for intact LL-37. The two hydrophobic domains in the long amphipathic helix (residues 2-31) of LL-37 separated by a hydrophilic residue serine 9 explain its cooperative binding to bacterial lipopolysaccharides (LPS). Both aromatic rings (F5, F6, F17, and F27) and interfacial basic amino acids of LL-37 directly interact with anionic phosphatidylglycerols (PG). Although the peptide sequences reported in the literature vary slightly, there is a consensus that the central helix of LL-37 is essential for disrupting superbugs (e.g., MRSA), bacterial biofilms, and viruses such as human immunodeficiency virus 1 (HIV-1) and respiratory syncytial virus (RSV). In the central helix, the central arginine R23 is of particular importance in binding to bacterial membranes or DNA. Mapping the functional roles of the cationic amino acids of the major antimicrobial region of LL-37 provides a basis for designing antimicrobial peptides with desired properties. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.
Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, NE 68198-6495, USA. Electronic address: gwang@unmc.edu.
Guangshun
G
Wang
Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, NE 68198-6495, USA.
Biswajit
B
Mishra
Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, Hamilton, Ontario L8S 4K1, Canada.
Raquel F
RF
Epand
Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, Hamilton, Ontario L8S 4K1, Canada.
Richard M
RM
Epand
D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism; D000998:Antiviral Agents / Q000737:chemistry*; D018441:Biofilms / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry*; D002463:Cell Membrane Permeability; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D000998:Antiviral Agents; D008051:Lipid Bilayers; D054804:Cathelicidins
Antimicrobial peptide; Cathelicidin; LL-37; Membranes; NMR; Structure–activity relationship