Proteins Fibrillation

Under specific and destabilizing conditions, any protein can self-assembly forming regular structures called amyloid fibrils. Native protein and amyloid aggregates can be seen as originating from a common population of partially unfolded, interconverting molecules. Amyloid fibrils are characterised by a common highly organized hydrogen-bonded structure which may give them an unique kinetic stability, high mechanical strength and stiffness. Amyloid fibrils generally consist of protofilaments, each around 2-5 nm in diameter, that twist together to form fibrils typically 7-13 nm wide; it is generally believed that amyloid fibrils possess a well-defined helicoidal distribution of β-sheet structure running perpendicularly around an elongation axis (cross-βstructure). Due to its medical implications, most of the efforts of the scientific community are addressed to the characterisation of amyloidal aggregation: several models for the mechanism of amyloid formation have been proposed most being based on nucleation-growth both homogeneous and heterogeneous including initial micelle formation, changes in protein conformation, and filament–filament association.

The evidence that aggregates of proteins not related to amyloidoses are cytotoxic and that strict analogies exist between the behaviour of cells in culture treated with misfolded non-pathogenic proteins and cells in pathogenic conditions, suggests that a common mechanism for cytotoxicity could exist. In this context, the structural definition of the cytotoxic species is complicated by the polymorphism of amyloid fibrils rising by multiple aggregation pathways promoted in different conditions: aggregated species rising from the same protein but characterised by distinct morphologies exhibit significantly different behaviours in cell cultures. For this reason, besides the structure of amyloid fibrils occurring during the aggregation kinetics, the mechanisms underlying the growth of amyloid fibrils represent one of the crucial points that need to be clarified. The study of such aspect is crucial for individuating fibril precursor and represents a first step towards the understanding of the primary sources and mechanisms of the amyloid-induced cellular toxicity.

List of related papers

• Andersen CB, Hicks MR, Vetri V, Vandahl B, Rahbek-Nielsen H, Thøgersen H, Thøgersen IB, Enghild JJ, Serpell LC, Rischel C, Otzen DE, J. Mol. Biol. (2010) In press: "Glucagon fibril polymorphism reflects differences in protofilament backbone structure."
• V. Vetri, R. Carrotta, P. Picone, M. Di Carlo and V. Militello, Biochim. Biophys. Acta – Protein & Proteomics 1804, (2010) 173-183: "Concanavalin A aggregation and toxicity on cell cultures"
• Foderà V., Cataldo S., Librizzi F., Pignataro B., Spiccia P., Leone M. , Journal of Physical Chemistry B, 113 (2009), 10830–10837: "Self-organization pathways and spatial heterogeneity in insulin amyloid fibrils formation"
• Foderà V., Librizzi F., Groenning M., van de Weert M. and Leone M. , J. of Phys. Chem. B 112 (2008), 3853-3858: "Secondary Nucleation and Accessible Surface in Insulin Amyloid Fibril Formation"
• V. Vetri, F. Librizzi, M. Leone and V. Militello, European Biophysics Journal 36 (2007), 733-741: "Effect of Succinylation on thermal induced amyloid formation in Concanavalin A"
• Librizzi F., Foderà V., Vetri V., Lo Presti C. and Leone M. , European Biophysics Journal 36 (2007), 711-715: "Effects of confinement on insulin amyloid fibrils formation"
• V. Vetri, C. Canale, A. Relini, F. Librizzi, V. Militello, A. Gliozzi and M. Leone , ” Biophys Chem. 125 (2007), 184-190: "Amyloid fibrils formation and amorphous aggregation in concanavalin A"