title: Truncation of a β-barrel scaffold dissociates intrinsic stability from its propensity to aggregation.
abstract: Δ98Δ is a functional all-β sheet variant of intestinal fatty acid binding protein (IFABP) that was generated by controlled proteolysis. This framework is useful to study the molecular determinants related to aggregation of β-barrel proteins. Albeit displaying increased conformational plasticity, Δ98Δ exhibits a nativelike β-barrel topology and is able to support a cooperative folding behavior. Here we present a comparative study of IFABP and Δ98Δ regarding their conformational perturbation and aggregation propensity triggered by trifluoroethanol. Both proteins share a common nucleation-elongation mechanism, whereby the rate-limiting step is the formation of stable dimeric nuclei followed by the association of monomers to the growing aggregates. Despite leading to a less stable structure, the extensive truncation of IFABP yields a form exhibiting a somewhat lower tendency to aggregate. This finding appears at odds with the established notion that a perturbation of the native compact fold should necessarily favor the population of aggregation-prone species. In addition to the aggregation propensity dictated by a given amino-acid sequence, our contention holds that long-range interactions might also play a major role in determining the overall aggregation propensity.
authors.affiliation: Department of Biological Chemistry and Institute of Biochemistry and Biophysics, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Lucrecia M
authors.initials: LM
authors.lastname: Curto
authors.forename: Carla R
authors.initials: CR
authors.lastname: Angelani
authors.forename: Julio J
authors.initials: JJ
authors.lastname: Caramelo
authors.forename: José M
authors.initials: JM
authors.lastname: Delfino
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D017510:Protein Folding; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D051381:Rats; D017384:Sequence Deletion; D014270:Trifluoroethanol / Q000494:pharmacology
chemical_list: D050556:Fatty Acid-Binding Proteins; D021122:Protein Subunits; D014270:Trifluoroethanol