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

PLoS One. 2017 Feb 10;12(2):e0170607. doi: 10.1371/journal.pone.0170607. eCollection 2017.


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.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Fatty Acid-Binding Proteins / chemistry*
  • Fatty Acid-Binding Proteins / metabolism
  • Protein Aggregates*
  • Protein Stability
  • Rats
  • Trifluoroethanol / chemistry


  • Fatty Acid-Binding Proteins
  • Protein Aggregates
  • Trifluoroethanol

Grant support

This research has been supported by grants to JMD and LMC from the University of Buenos Aires (UBACyT Q-405), the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET PIP 0540) and the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT PICT 2014-2757).