NMR structure of the cathelicidin-derived human antimicrobial peptide LL-37 in dodecylphosphocholine micelles

被引:157
作者
Porcelli, Fernando [2 ,3 ,4 ]
Verardi, Raffaello [2 ,3 ]
Shi, Lei [2 ,3 ]
Henzler-Wildman, Katherine A. [1 ]
Ramamoorthy, Ayyalusamy [1 ]
Veglia, Gianluigi [2 ,3 ]
机构
[1] Univ Michigan, Dept Chem & Biochem, Ann Arbor, MI 48109 USA
[2] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA
[3] Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA
[4] Univ Tuscia, Dept Environm Sci Di SA, Viterbo, Italy
关键词
D O I
10.1021/bi702036s
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 120 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.
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页码:5565 / 5572
页数:8
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