NMR structure of the cathelicidin-derived human antimicrobial peptide LL-37 in dodecylphosphocholine micelles.
LL-37 is the only cathelicidin-derived polypeptide found in humans. Its eclectic function makes this peptide one of the most intriguing chemical defense agents, with crucial roles in moderating inflammation, promoting wound healing, and boosting the human immune system. LL-37 kills both prokaryotic and eukaryotic cells through physical interaction with cell membranes. In order to study its active conformation in membranes, we have reconstituted LL-37 into dodecylphosphocholine (DPC) micelles and determined its three-dimensional structure. We found that, under our experimental conditions, this peptide adopts a helix-break-helix conformation. Both the N- and C-termini are unstructured and solvent exposed. The N-terminal helical domain is more dynamic, while the C-terminal helix is more solvent protected and structured (high density of NOEs, slow H/D exchange). When it interacts with DPC, LL-37 is adsorbed on the surface of the micelle with the hydrophilic face exposed to the water phase and the hydrophobic face buried in the micelle hydrocarbon region. The break between the helices is positioned at K12 and is probably stabilized by a hydrophobic cluster formed by I13, F17, and I20 in addition to a salt bridge between K12 and E16. These results support the proposed nonpore carpet-like mechanism of action, in agreement with the solid-state NMR studies, and pave the way for understanding the function of the mature LL-37 at the atomic level.
Porcelli
Fernando
F
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Verardi
Raffaello
R
Shi
Lei
L
Henzler-Wildman
Katherine A
KA
Ramamoorthy
Ayyalusamy
A
Veglia
Gianluigi
G
D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D006801:Humans; D008823:Micelles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry; D017434:Protein Structure, Tertiary; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D008823:Micelles; D010767:Phosphorylcholine; C028810:dodecylphosphocholine; D054804:Cathelicidins