NMR structure of the cathelicidin-derived human antimicrobial peptide LL-37 in dodecylphosphocholine micelles
NMR structure of the cathelicidin-derived human antimicrobial peptide LL-37 in dodecylphosphocholine micelles
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DOI：
10.1021/bi702036s
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发表时间：
2008-05-20
期刊：
影响因子：
2.9
通讯作者：
Veglia, Gianluigi
中科院分区：
文献类型：
--
作者：
Porcelli, Fernando;Verardi, Raffaello;Veglia, Gianluigi
IL-37是在人类体内发现的唯一一种由中草药衍生的多肽。它的折衷功能使这种多肽成为最耐人寻味的化学防御剂之一，在缓解炎症、促进伤口愈合和增强人体免疫系统方面发挥着关键作用。LL-37通过与细胞膜的物理作用杀死原核细胞和真核细胞。为了研究其在膜中的活性构象，我们将其重组为十二烷基磷胆碱(DPC)胶束，并测定了其三维结构。我们发现，在我们的实验条件下，该肽采用螺旋-断裂-螺旋构象。N-末端和C-末端都是无结构的，并暴露在溶剂中。N-末端螺旋结构域更具动态，而C-末端螺旋更具溶剂保护和结构化(NOE密度高，H/D交换缓慢)。当它与DPC相互作用时，LL-37被吸附在胶束表面，亲水面暴露在水相中，疏水面埋在胶束碳氢区。螺旋之间的断裂位于K12，除了K12和E16之间的盐桥外，可能还被I13、F17和120形成的疏水簇稳定。这些结果支持提出的无孔地毯状作用机理，与固体核磁共振研究一致，并为在原子水平上理解成熟的LL-37的功能铺平了道路。
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.