title: Expanding the repertoire of amyloid polymorphs by co-polymerization of related protein precursors.
abstract: Amyloid fibrils can be generated from proteins with diverse sequences and folds. Although amyloid fibrils assembled in vitro commonly involve a single protein precursor, fibrils formed in vivo can contain more than one protein sequence. How fibril structure and stability differ in fibrils composed of single proteins (homopolymeric fibrils) from those generated by co-polymerization of more than one protein sequence (heteropolymeric fibrils) is poorly understood. Here we compare the structure and stability of homo and heteropolymeric fibrils formed from human β2-microglobulin and its truncated variant ΔN6. We use an array of approaches (limited proteolysis, magic angle spinning NMR, Fourier transform infrared spectroscopy, and fluorescence) combined with measurements of thermodynamic stability to characterize the different fibril types. The results reveal fibrils with different structural properties, different side-chain packing, and strikingly different stabilities. These findings demonstrate how co-polymerization of related precursor sequences can expand the repertoire of structural and thermodynamic polymorphism in amyloid fibrils to an extent that is greater than that obtained by polymerization of a single precursor alone.
authors: Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors: Claire J
authors: CJ
authors: Sarell
authors: Lucy A
authors: LA
authors: Woods
authors: Yongchao
authors: Y
authors: Su
authors: Galia T
authors: GT
authors: Debelouchina
authors: Alison E
authors: AE
authors: Ashcroft
authors: Robert G
authors: RG
authors: Griffin
authors: Peter G
authors: PG
authors: Stockley
authors: Sheena E
authors: SE
authors: Radford
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D050505:Mutant Proteins / Q000737:chemistry* / Q000378:metabolism; D009154:Mutation; D058105:Polymerization; D011498:Protein Precursors / Q000737:chemistry* / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000682:Amyloid; D004220:Disulfides; D050505:Mutant Proteins; D011498:Protein Precursors; D001613:beta 2-Microglobulin