title: A folding-dependent mechanism of antimicrobial peptide resistance to degradation unveiled by solution structure of distinctin.
abstract: 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.
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, Comprensorio Olivetti, Edificio 70, I-80078 Pozzuoli (Naples), Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Raimondo
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Andreotti
authors.forename: Nathalie
authors.initials: N
authors.lastname: Saint
authors.forename: Pietro
authors.initials: P
authors.lastname: Amodeo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Renzone
authors.forename: Marina
authors.initials: M
authors.lastname: Sanseverino
authors.forename: Ivana
authors.initials: I
authors.lastname: Zocchi
authors.forename: Gerard
authors.initials: G
authors.lastname: Molle
authors.forename: Andrea
authors.initials: A
authors.lastname: Motta
authors.forename: Andrea
authors.initials: A
authors.lastname: Scaloni
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001001:Anura / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D019281:Dimerization; D007473:Ion Channels / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010447:Peptide Hydrolases / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D014867:Water / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D007473:Ion Channels; D014867:Water; D010447:Peptide Hydrolases