1.C.108 The Pore-forming Dermcidin (Dermcidin) Family

Song et al. (2013) presented the X-ray crystal structure as well as solid-state NMR spectroscopy, electrophysiology and MD simulations of human dermcidin (DCD) (also called preproteolysin) in membranes. These studies revealed the antibiotic mechanism of this major human antimicrobial which suppresses Staphylococcus aureus growth on epidermal surfaces. Dermcidin forms an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidated the unusual membrane permeation pathway for ions and showed adjustment of the pore to various membranes. These study unraveled the comprehensive mechanism for the membrane-disruptive action of this mammalian host-defense peptide at the atomic level (Song et al., 2013).

Bilayers composed of various lipids (DMPC, DPPC, and DSPC) with different thicknesses result in different orientations of the DCD oligomer; the thicker the bilayer, the less tilted the channel (Song et al. 2019). Cholesterol makes the bilayers more rigid and thicker, which also affects the orientation of the channel. The predicted conductance of the channel is related to its orientation in the lipid bilayer: the larger the tilt, the larger the conductance. Thus, thicker, cholesterol-rich membranes show lower conductance than that of thinner membranes (Song et al. 2019).


 

References:

Song, C., B.L. de Groot, and M.S.P. Sansom. (2019). Lipid Bilayer Composition Influences the Activity of the Antimicrobial Peptide Dermcidin Channel. Biophys. J. 116: 1658-1666.

Song, C., C. Weichbrodt, E.S. Salnikov, M. Dynowski, B.O. Forsberg, B. Bechinger, C. Steinem, B.L. de Groot, U. Zachariae, and K. Zeth. (2013). Crystal structure and functional mechanism of a human antimicrobial membrane channel. Proc. Natl. Acad. Sci. USA 110: 4586-4591.

Zeth, K. and E. Sancho-Vaello. (2017). The Human Antimicrobial Peptides Dermcidin and LL-37 Show Novel Distinct Pathways in Membrane Interactions. Front Chem 5: 86.

Examples:

TC#NameOrganismal TypeExample
1.C.108.1.1

Antimicrobial dermcidin, DCD.  Based on 3-d structural data, dermcidin forms an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidated the unusual membrane permeation pathway for ions and showed adjustment of the pore to various membranes (Song et al. 2013). DCD assembles in solution into a hexameric pre-channel complex before  targeting the membrane and integration, the complex follows a deviation of the barrel stave model (Zeth and Sancho-Vaello 2017). The tilt angle and the conductance is determined by the membrane thickness and the cholesterol composition (Song et al. 2019). A soluble 48 residue fragment has been structurally characterized (PDB: 2KSG_A). Membrane interactions and pore formation have been investigated for α-helical AMPs leading to the formulation of three basic mechanistic models: the barrel stave, toroidal, and carpet models. Human cathelicidin (LL-37) and dermcidin (DCD) are α-helical, and their structures have been solved at atomic resolution. DCD assembles in solution into a hexameric pre-channel complex before  actual membrane targeting and integration steps occur, and the complex follows a deviation of the barrel stave model (Zeth and Sancho-Vaello 2017).

Animals

Dermcidin of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
1.C.108.2.1

Lacritin of 137 aas and 1 N-terminal TMS.  The crystal structure is available for the C-terminal 48 aas (2KSG A).

Animals

Lacritin of Pongo abelii

 
1.C.108.2.2

Extracellular glycoprotein lacritin-like isoform X2 of 111 aas and 1 N-terminal TMS.

Lacritin-like peptide of Equus przewalskii

 
1.C.108.2.3

Extracellular glycoprotein lacritin isoform X1of 119 aas and 1 N-terminal TM

Lacritin-like protein of Acinonyx jubatus

 
1.C.108.2.4

Extracellular glycoprotein lacritin of 109 aas and 1 N-terminal TMS.

lacritin of Myotis lucifugus

 
Examples:

TC#NameOrganismal TypeExample
1.C.108.3.1

Hypothetical protein

Animals

HP of Homo sapiens