Truncation of a beta-Barrel Scaffold Dissociates Intrinsic Stability from Its Propensity to Aggregation

CURTO LM; ANGELANI CR; CARAMELO JJ; DELFINO JM

BIOPHYSICAL JOURNAL

CELL PRESS

Lugar: United States; Año: 2012 vol. 103 p. 1929 - 1939

0006-3495

Delta98Delta is a functional all-beta 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 b-barrel proteins. Albeit displaying increased conformational plasticity, Delta98Delta exhibits a nativelike b-barrel topology and is able to support a cooperative folding behavior. Here we present a comparative study of IFABP and Delta98Delta 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.