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

Many bioactive peptides, presenting an unstructured conformationin aqueous solution, are made resistant to degradation byposttranslational modifications. Here, we describe how molecularoligomerization in aqueous solution can generate a still unknowntransport form for amphipathic peptides, which is more compactand resistant to proteases than forms related to any possiblemonomer. This phenomenon emerged from 3D structure, function,and degradation properties of distinctin, a heterodimeric antimicrobialcompound consisting of two peptide chains linked by adisulfide bond. After homodimerization in water, this peptideexhibited a fold consisting of a symmetrical full-parallel four-helixbundle, with a well secluded hydrophobic core and exposed basicresidues. This fold significantly stabilizes distinctin against proteasescompared with other linear amphipathic peptides, withoutaffecting its antimicrobial, hemolytic, and ion-channel formationproperties after membrane interaction. This full-parallel helicalorientation represents a perfect compromise between formationof a stable structure in water and requirement of a drastic structuralrearrangement in membranes to elicit antimicrobial potential.Thus, distinctin can be claimed as a prototype of a previouslyunrecognized class of antimicrobial derivatives. These results suggesta critical revision of the role of peptide oligomerizationwhenever solubility or resistance to proteases is known to affectbiological properties.