Structural basis for the bacterial membrane insertion of dermcidin peptide, DCD-1L

Sci Rep. 2017 Oct 24;7(1):13923. doi: 10.1038/s41598-017-13600-z.

Abstract

Human dermcidin (DCD) is an antimicrobial peptide secreted constitutively by sweat glands. The anionic derivative, DCD-1L, comprises of the N-terminal 47 residues of DCD and one additional leucine residue. A previous NMR structure of DCD-1L in 50% TFE showed a partial helical conformation, and its crystal structure in the presence of Zn2+ outlined a hexameric linear α-helical bundle. Three different models to describe membrane insertion were proposed but no conclusion was drawn. In the current study, the NMR structure of DCD-1L in SDS micelles showed an "L-shaped" molecule with three fully formed α-helices connected by flexible turns. Formation of these helices in DCD-1L in the presence of POPG vesicles suggests that the acidic C-terminal region of DCD-1L can suppress the binding of DCD-1L to POPG vesicles at basic but not acidic pH. Mutation of charged residues on the N-terminal and C-terminal regions of DCD-1L cause differences in POPG binding, suggesting distinct functional roles for these two regions. Charged residues from these two regions are also found to differentially affect Zn2+ coordination and aggregation of DCD-1L in the absence or presence of SDS, as monitored by 1D NMR. Our data agrees with one of the three models proposed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacteria / cytology*
  • Cell Membrane / metabolism*
  • Humans
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Peptides / chemistry*
  • Peptides / genetics
  • Peptides / metabolism*
  • Phosphatidylglycerols / metabolism
  • Protein Aggregates / drug effects
  • Protein Conformation, alpha-Helical
  • Sodium Dodecyl Sulfate / chemistry
  • Zinc / pharmacology

Substances

  • Peptides
  • Phosphatidylglycerols
  • Protein Aggregates
  • dermcidin
  • Sodium Dodecyl Sulfate
  • 1-palmitoyl-2-oleoylglycero-3-phosphoglycerol
  • Zinc