IQUIFIB   02644
INSTITUTO DE QUIMICA Y FISICOQUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
ON HOW STABLE β-BARRELS BECOME PROPENSE TO AGGREGATION
Autor/es:
. LUCRECIA MA. CURTO, CARLA R. ANGELANI, INÉS S. CABANAS, JULIO J. CARAMELO AND JOSÉ M. DELFINO.
Lugar:
Salisbury Cove, Maine
Reunión:
Congreso; Mechanobiology of Proteins and Cells Meeting; 2013
Institución organizadora:
Biophysical Society
Resumen:
The genesis of protein biofibrils underlies both functional cell phenomena as well as aberrant disease-related polymerization. Understanding this self-assembly process remains a key challenge in biology. Particularly, a diverse array of polypeptides gives rise to amyloid cross-β structure. In this context, the ?β-clam? of intestinal fatty acid binding protein (IFABP) and its variants Δ98Δ and Δ78Δ (29-126 and 29-106 stretches of IFABP, respectively) offer a rare opportunity for investigating the transition between these motifs. Albeit displaying increased plasticity, the abridged forms exhibit a native-like β-barrel topology supporting cooperative folding. Whereas IFABP and Δ98Δ are monomers in solution, Δ78Δ adopts a dimeric structure. Challenging these scaffolds with 25% v/v trifluoroethanol (TFE) readily triggers aggregation. The evolution of turbidity measurements demonstrates a common scaling behavior of the kinetic parameters, pointing to a primary nucleation-elongation mechanism, whereby the stabilization of dimeric nuclei precedes the association of protein to the growing aggregates. Congo Red and Thioflavin-T binding as well as imaging by TEM suggest amyloid-like character. A common tenet holds that overall aggregation propensity is dictated by relatively short amino acid sequences. Accordingly, a consensus prediction for aggregationprone peptides identifies the shared segment 58-71. Intrinsic stability (IFABP>Δ78Δ>Δ98Δ) do not bear a straightforward correlation with aggregation tendency (Δ78Δ>IFABP>Δ98Δ). These findings appear at odds with the established notion that a perturbation of the native fold should necessarily favor the population of aggregation-prone species. Interestingly, exposure to sub-aggregating concentration of TFE (10% v/v) reveals the coalescence of all three proteins into conformations richer in β content and more akin in stability, as revealed by guanidinium chloride and temperature induced unfolding. All in all, overall aggregation propensity might not only depend on local amino acid sequence, but also on the persistence of key spatial interactions.