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

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

Rio de Janeiro

Congreso; V Latin American Protein Society Meeting (V LAPS); 2016

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). With the aid of truncated but functional all-β sheet constructs of this protein (Δ98Δ and Δ78Δ), we were able to advance the knowledge on key determinants related to aggregation (1, 2). Albeit displaying increased conformational plasticity, these variants exhibit a native-like β-barrel topology and are able to support a cooperative folding behavior. 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 of these proteins (ΔG°H2O: IFABP≥Δ78Δ>Δ98Δ) does not bear a straightforward correlation with their aggregation propensity (Δ78Δ>IFABP≥Δ98Δ) triggered by the co-solvent trifluoroethanol (TFE)(3). In view of this fact, we found it more insightful to delve into the connection between aggregation and stability under sub-aggregating conditions, i.e. as TFE is added up to 10-15 % v/v. Interestingly, this treatment brings about the coalescence of all three proteins assayed into a common conformational ensemble more akin in stability. This scenario likely mimics the accrual of aggregation-prone species in the population, an early critical event for the development of fibrillation. 1. LM Curto, CR Angelani, JM Delfino (2015) Prostaglandins Leukot Essent Fat Acids 93, 37?43 2. CR Angelani, LM Curto, IS Cabanas, JJ Caramelo, VN Uversky, JM Delfino (2014) Biochim Biophys Acta - Proteins Proteomics 1844, 1599?1607 3. LM Curto, CR Angelani, JJ Caramelo, JM Delfino (2012) Biophys J 103, 1929?1939