Unidad de Biofisica, Centro Mixto Consejo Superior de Investigaciones Científicas-Universidad del País Vasco/Euskal Herriko Unibertsitatea (CSIC,UPV/EHU), Barrio Sarriena s/n, Leioa, Bizkaia, Spain.
Genomic Research Laboratory, Department of Medical Specialities, Geneva University Hospitals, University of Geneva, Genève, Switzerland.
Sci Rep. 2017 Nov 13;7(1):15371. doi: 10.1038/s41598-017-14206-1.
Antimicrobial peptides as part of the mammalian innate immune system target and remove major bacterial pathogens, often through irreversible damage of their cellular membranes. To explore the mechanism by which the important cathelicidin peptide LL-37 of the human innate immune system interacts with membranes, we performed biochemical, biophysical and structural studies. The crystal structure of LL-37 displays dimers of anti-parallel helices and the formation of amphipathic surfaces. Peptide-detergent interactions introduce remodeling of this structure after occupation of defined hydrophobic sites at the dimer interface. Furthermore, hydrophobic nests are shaped between dimer structures providing another scaffold enclosing detergents. Both scaffolds underline the potential of LL-37 to form defined peptide-lipid complexes in vivo. After adopting the activated peptide conformation LL-37 can polymerize and selectively extract bacterial lipids whereby the membrane is destabilized. The supramolecular fibril-like architectures formed in crystals can be reproduced in a peptide-lipid system after nanogold-labelled LL-37 interacted with lipid vesicles as followed by electron microscopy. We suggest that these supramolecular structures represent the LL-37-membrane active state. Collectively, our study provides new insights into the fascinating plasticity of LL-37 demonstrated at atomic resolution and opens the venue for LL-37-based molecules as novel antibiotics.
抗菌肽作为哺乳动物先天免疫系统的一部分，靶向并清除主要的细菌病原体，通常通过不可逆地破坏其细胞膜来实现。为了探索人类先天免疫系统中重要的抗菌肽 LL-37 与膜相互作用的机制，我们进行了生化、生物物理和结构研究。LL-37 的晶体结构显示出反平行螺旋的二聚体和形成两亲性表面。肽-去污剂相互作用在占据二聚体界面上定义的疏水位点后，会引起结构的重排。此外，在二聚体结构之间形成疏水巢，为包围去污剂提供了另一个支架。这两个支架强调了 LL-37 在体内形成特定肽-脂质复合物的潜力。在采用激活肽构象后，LL-37 可以聚合并选择性地提取细菌脂质，从而使膜不稳定。在纳米金标记的 LL-37 与脂质囊泡相互作用后，在肽-脂质系统中可以重现晶体中形成的超分子原纤维样结构，随后通过电子显微镜进行观察。我们认为这些超分子结构代表了 LL-37 与膜相互作用的活性状态。总的来说，我们的研究提供了新的见解，揭示了 LL-37 在原子分辨率下表现出的惊人的可塑性，并为基于 LL-37 的分子作为新型抗生素开辟了道路。
