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Abstract
Mammals protect themselves from inflammation triggered by microorganisms through secretion of antimicrobial peptides (AMPs). One mechanism by which AMPs kill bacterial cells is perforating their membranes. Membrane interactions and pore formation were investigated for α-helical AMPs leading to the formulation of three basic mechanistic models: the barrel stave, toroidal, and carpet model. One major drawback of these models is their simplicity. They do not reflect the real in vitro and in vivo conditions. To challenge and refine these models using a structure-based approach we set out to investigate how human cathelicidin (LL-37) and dermcidin (DCD) interact with membranes. Both peptides are α-helical and their structures have been solved at atomic resolution. DCD assembles in solution into a hexameric pre-channel complex before the actual membrane targeting and integration step can occur, and the complex follows a deviation of the barrel stave model. LL-37 interacts with lipids and shows the formation of oligomers generating fibril-like supramolecular structures on membranes. LL-37 further assembles into transmembrane pores with yet unknown structure expressing a deviation of the toroidal pore model. Both of their specific targeting mechanisms will be discussed in the context of the “old” models propagated in the literature.
Highlights
There is no doubt that true mechanisms in vivo in the context of bacterial cell walls are even more complex, and future work needs to initiate studies on the direct interactions of AMPs with the bacterial cell
DCD and LL-37 are only two selected examples of AMPs, and such do not represent the broadness of mechanisms of how AMPs perturb bacterial membranes
LL-37 activity and killing mechanisms harbors many secrets e.g.:. How this peptide interacts with LPS and LTA, and if these molecules are extracted from the membrane to gain access to the cell?
Summary
Antimicrobial peptides evolved during an early stage of the mammalian evolution and represent ancient molecules optimized through their co-evolution with bacteria (Peschel and Sahl, 2006). This figure is reprinted with permission from Brogden (2005). In the second step, according to our own data and the data of others implies that LL-37 can interact with membranes or even with individual lipid head groups via a multi-step mechanism (Scientific reports in press; Shahmiri et al, 2016; Figure 2D) This mechanism is more complicated than the simple toroidal model, where the monomeric peptide assembles on the membrane to form holes on lipid-peptide complexes (Ludtke et al, 1996; Matsuzaki et al, 1996). LL-37 forms channels or pores in membranes to destroy the transmembrane potential but it is unknown if these channels express a peptide-lipid stabilized architecture (Lee et al, 2011; Figure 2D)
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