title: Structural coalescence underlies the aggregation propensity of a β-barrel protein motif.
abstract: A clear understanding of the structural foundations underlying protein aggregation is an elusive goal of central biomedical importance. A step toward this aim is exemplified by the β-barrel motif represented by the intestinal fatty acid binding protein (IFABP) and two abridged all-β sheet forms (Δ98Δ and Δ78Δ). At odds with the established notion that a perturbation of the native fold should necessarily favor a buildup of intermediate forms with an enhanced tendency to aggregate, the intrinsic stability (ΔG°H2O) of these proteins does not bear a straightforward correlation with their trifluoroethanol (TFE)-induced aggregation propensity. In view of this fact, we found it more insightful to delve into the connection between structure and stability under sub-aggregating conditions (10% TFE). In the absence of the co-solvent, the abridged variants display a common native-like region decorated with a disordered C-terminal stretch. Upon TFE addition, an increase in secondary structure content is observed, assimilating them to the parent protein. In this sense, TFE perturbs a common native like region while exerting a global compaction effect. Importantly, in all cases, fatty acid binding function is preserved. Interestingly, energetic as well as structural diversity in aqueous solution evolves into a common conformational ensemble more akin in stability. These facts reconcile apparent paradoxical findings related to stability and rates of aggregation. This scenario likely mimics the accrual of aggregation-prone species in the population, an early critical event for the development of fibrillation.
authors.affiliation: Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Biológica, Buenos Aires, Argentina.|Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Carla R
authors.initials: CR
authors.lastname: Angelani
authors.affiliation: Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Buenos Aires, Argentina.|Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.|Fundación Instituto Leloir, Buenos Aires, Argentina.
authors.forename: Julio J
authors.initials: JJ
authors.lastname: Caramelo
authors.affiliation: Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Biológica, Buenos Aires, Argentina.|Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Lucrecia M
authors.initials: LM
authors.lastname: Curto
authors.affiliation: Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Biológica, Buenos Aires, Argentina.|Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: José M
authors.initials: JM
authors.lastname: Delfino
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D066329:Protein Aggregates; D055550:Protein Stability; D051381:Rats; D014270:Trifluoroethanol / Q000737:chemistry
chemical_list: D050556:Fatty Acid-Binding Proteins; D066329:Protein Aggregates; D014270:Trifluoroethanol