蛋白质聚集的情况.pptVIP

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2017-09-21 发布于福建
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蛋白质聚集的情况.ppt

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Scenarios for Protein Aggregation Illustrations using A? peptides and PrPC as examples Global Structure of amyloid fibrils diameter = 4-12 nm (electron microscopy) cross-b structure (strands perpendicular to long axis of fibril) 4.7 ? inter-strand spacing (along axis) 9 ? inter-sheet spacing (perpendicular on axis) twist between adjacent strands 2-5 protofilaments (overall helical twist) (X-ray fiber diffraction,solid state NMR) Energy landscape for monomeric folding Aggregation Linked to diseases Protein deposition diseases * transmissible spongiform encephalopathies (TSE; Mad Cow Disease) * Alzheimer’s disease, Parkinson’s disease * diabetes (type II) All these diseases = related to misfolding and protein aggregation Misfolding into multiple amyloid conformations (strains) Examples: prion proteins (TSE), Alzheimer’s, CWD Scenarios for Fibrillization Cascade of events to Fibrils Scenario I (Partial unfolding/ordering) Heterogeneous Nucleation and Growth A? Sequence Ab-peptide in vivo is a metabolic product of precursor protein A?16-22 For Scenario I Mechanism and Assembly Pathways Sequence Effects Role of water Fragment has CHC Interplay of hydrophobic/electrostatic effects Trimer Structurefrom MD Dominant assembly pathway involves?-helical intermediate Origin of ?-helical Intermediate C ? C* Peptides Interact Hydrophobic andcharged residuesstabilize oligomers Mutations in the CHC destabilize A?16-22 Oligomers Structural orientation requires charged residues Electrostatics interactions essential in amyloid formation: Charged states Templated assembly Important structural motifs in Ab-peptide monomer and fibrils Scenario II (Global unfolding of PrPC) Mechanism of assembly and propagation Question and Hypothesis NMR Structure of Cellular form (PrPC) PrPC: 45% a, 8% b PrPSc(90-231): 25% a, 48% b Predictions using Bioinformatics certain regions besides (90-120) must undergo conformational tra