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

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 Zn 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 Zn 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.