TRUNCATION OF A b-BARREL SCAFFOLD DISSOCIATES INTRINSIC STABILITY FROM ITS PROPENSITY TO AGGREGATION

CURTO L.M.; ANGELANI, C.R.; CARAMELO, J.J.; DELFINO J.M.

BIOPHYSICAL JOURNAL

CELL PRESS

Lugar: United States; Año: 2012 p. 1929 - 1939

0006-3495

Δ98Δ is a functional all-β sheet variant of IFABP (intestinal fatty acid binding protein) that was generated by controlled proteolysis. This framework is useful to study the molecular determinants related to aggregation of β-barrel proteins. Albeit displaying increased conformational plasticity, Δ98Δ exhibits a native-like β-barrel topology and is able to support a cooperative folding behavior. Here we present a comparative study of IFABP and Δ98Δ 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.