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.
Highlights
IntroductionSuch information will likely be of great use to shed light on normal processes or-when the outcome goes astray- on the origin of pathologies
Achieving full understanding of the mechanism of protein aggregation will represent a breakthrough in the context of both physiological and pathological phenomena occurring in nature.PLOS ONE | DOI:10.1371/journal.pone.0170607 February 10, 2017Conformational coalescence of a β-barrelAbbreviations: Δ78Δ, a truncated variant of IFABP corresponding to the fragment 29–106 of the parent protein; Δ98Δ, a truncated variant of IFABP corresponding to the fragment 29–126 of the parent protein; λmax, position of the maximum wavelength of fluorescence emission; IFABP, intestinal fatty acid binding protein; TFE, 2,2,2trifluoroethanol.Such information will likely be of great use to shed light on normal processes or-when the outcome goes astray- on the origin of pathologies
At odds with the common notion that a perturbation of the native fold should necessarily favor the population of aggregation-prone species, we found that even though these proteins share a common amyloidogenic stretch, their intrinsic stability (ΔGH2O: IFABP!Δ78Δ>Δ98Δ) does not bear a straightforward correlation with their aggregation propensity triggered by 25% v/v 2,2,2-trifluoroethanol
Summary
Such information will likely be of great use to shed light on normal processes or-when the outcome goes astray- on the origin of pathologies. This new comprehension will be of fundamental value in establishing modes of intervention on aggregation diseases with effector molecules, hopefully leading to the development of new therapies [1,2]. There are few proteins of the β-class which are useful as model systems for protein engineering, mainly due to their conspicuous tendency to aggregate For this reason, the intestinal fatty acid binding protein (IFABP) family arises as a very helpful target that allows molecular intervention on those structural determinants underlying conformational change, folding, misfolding and aggregation
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