A folding-dependent mechanism of antimicrobial peptide resistance to degradation unveiled by solution structure of distinctin

Many bioactive peptides, presenting an unstructured conformation
in aqueous solution, are made resistant to degradation by
posttranslational modifications. Here, we describe how molecular
oligomerization in aqueous solution can generate a still unknown
transport form for amphipathic peptides, which is more compact
and resistant to proteases than forms related to any possible
monomer. This phenomenon emerged from 3D structure, function,
and degradation properties of distinctin, a heterodimeric antimicrobial
compound consisting of two peptide chains linked by a
disulfide bond. After homodimerization in water, this peptide
exhibited a fold consisting of a symmetrical full-parallel four-helix
bundle, with a well secluded hydrophobic core and exposed basic
residues. This fold significantly stabilizes distinctin against proteases
compared with other linear amphipathic peptides, without
affecting its antimicrobial, hemolytic, and ion-channel formation
properties after membrane interaction. This full-parallel helical
orientation represents a perfect compromise between formation
of a stable structure in water and requirement of a drastic structural
rearrangement in membranes to elicit antimicrobial potential.
Thus, distinctin can be claimed as a prototype of a previously
unrecognized class of antimicrobial derivatives. These results suggest
a critical revision of the role of peptide oligomerization
whenever solubility or resistance to proteases is known to affect
biological properties.