title: Solid-state NMR reveals differences in the packing arrangements of peptide aggregates derived from the aortic amyloid polypeptide medin.
abstract: Several polypeptides aggregate into insoluble amyloid fibrils associated with pathologies such as Alzheimer's disease, Parkinson's disease and type 2 diabetes. Understanding the structural and sequential motifs that drive fibrillisation may assist in the discovery and refinement of effective therapies. Here we investigate the effects of three predicted amyloidogenic regions on the structure of aggregates formed by medin, a poorly characterised polypeptide associated with aortic medial amyloidosis. Solid-state NMR is used to compare the dynamics and sheet packing arrangement of the C-terminal region encompassing residues F(43) GSV within full-length medin (Med(1-50) ) and two shorter peptide fragments, Med(30-50) and Med(42-49) , lacking specific sequences predicted to be amyloidogenic.(.) Results show that all three peptides have different aggregate morphologies, and Med(30-50) and Med(1-50) have different sheet packing arrangements and dynamics to Med(42-49) . These results imply that at least two of the three predicted amyloidogenic regions are required for the formation and elongation of medin fibres observed in the disease state.
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK.
authors.forename: Hannah A
authors.initials: HA
authors.lastname: Davies
authors.forename: Jillian
authors.initials: J
authors.lastname: Madine
authors.forename: David A
authors.initials: DA
authors.lastname: Middleton
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D000954:Antigens, Surface / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D001011:Aorta / Q000378:metabolism* / Q000503:physiopathology; D052160:Benzothiazoles; D015415:Biomarkers / Q000737:chemistry* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008854:Microscopy, Electron; D008894:Milk Proteins / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism* / Q000648:ultrastructure; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000032:analysis
chemical_list: D000682:Amyloid; D000954:Antigens, Surface; D052160:Benzothiazoles; D015415:Biomarkers; C098942:MFGE8 protein, human; D008894:Milk Proteins; D010446:Peptide Fragments; D013844:Thiazoles; C009462:thioflavin T