Site-Specific Structure and Dynamics of Polyglutamine-Containing Amyloid Fibrils and the Caveolin Scaffolding Domain by Magic Angle Spinning Solid-State NMR

摘要: Protein assemblies and membrane associations play important roles in health disease. Structural studies of these biological complexes are thus vital, but often unfeasible by conventional tools structural biology. Solid-state NMR (ssNMR) has made possible atomic-level large, insoluble, non-crystalline systems, such as amyloid fibrils proteins. Amyloid associated with at least 20 human diseases, making aspects their formation crucial to understanding aggregation pathways. Huntington’s disease (HD) is caused an expansion beyond a threshold the polyglutamine (polyQ) domain Exon 1 huntingtin protein (htt). The 17-residue N-terminal segment (httNT) initiates fibril helps stabilize oligomers fibrils. On contrary, polyPro C-terminal polyQ reduces aggregation. In this thesis, magic-angle spinning (MAS) ssNMR was used elucidate atomic-resolution structure dynamics its flanking domains polyQ-containing amyloid-like More than 25% proteins Caveolin-1 (Cav1) found cholesterol-rich membranes that forms caveolae, curved cave-like invaginations plasma membrane, implicated muscular diseases cancers. caveolin-scaffolding (CSD) Cav1 responsible for cholesterol-recognition oligomerization form caveolae. MAS static molecular CSD perturbation lipid bilayer environment. These results allow more thorough role caveolae formation.