Structural coalescence underlies the aggregation propensity of a β-barrel protein motif

• Published in: PloS one 2017-02, Vol.12 (2), p.e0170607-e0170607
• Main Authors: Angelani, Carla R, Caramelo, Julio J, Curto, Lucrecia M, Delfino, José M
• Format: Article
• Language: English
• Subjects: Agglomeration; Amino Acid Motifs; Amino acids; Animals; Binding; Biochemistry; Bioinformatics; Biology and Life Sciences; Coalescence; Coalescing; Fatty acid-binding protein; Fatty Acid-Binding Proteins - chemistry; Fatty Acid-Binding Proteins - metabolism; Fatty acids; Fibrillation; Intestine; Ligands; Neural networks; Physical Sciences; Protein Aggregates; Protein interaction; Protein Stability; Protein structure; Proteins; Rats; Research and Analysis Methods; Secondary structure; Structural stability; Trifluoroethanol; Trifluoroethanol - chemistry
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0170607

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.