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Truncation of a ?-barrel scaffold dissociates intrinsic stability from its propensity to aggregation.

ABSTRACT: ?98? is a functional all-? 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 ?-barrel proteins. Albeit displaying increased conformational plasticity, ?98? exhibits a nativelike ?-barrel topology and is able to support a cooperative folding behavior. Here we present a comparative study of IFABP and ?98? 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.


PROVIDER: S-EPMC3491725 | BioStudies | 2012-01-01

REPOSITORIES: biostudies

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