Polymorphic Fibrillation of the Destabilized Fourth Fasciclin-1 Domain Mutant A546T of the Transforming Growth Factor-β-induced Protein (TGFBIp) Occurs through Multiple Pathways with Different Oligomeric Intermediates

摘要: Mutations in the transforming growth factor β-induced protein (TGFBIp) are linked to development of corneal dystrophies which abnormal deposition cornea leads a loss transparency and ultimately blindness. Different mutations give rise phenotypically distinct dystrophies. Most located fourth fasciclin-1 domain (FAS1–4). The amino acid substitution A546T FAS1–4 is lattice dystrophy with amyloid deposits superficial deep stroma, classifying it as an disease. Here we provide detailed description fibrillation isolated carrying substitution. significant destabilization induces partially folded structure increased surface exposure hydrophobic patches. mutation also two fibril morphologies. Long straight fibrils composed pure β-sheet formed at lower concentrations, whereas short curly containing mixture α-helical structures higher concentrations. formation preceded by small number oligomeric species high membrane permeabilization potential rapid formation. long more slowly through progressively bigger oligomers that lose their proceeds beyond lag phase. These different classes associated biochemical differences may lead clinical symptoms mutation.