Atomic structure and hierarchical assembly of a cross-β amyloid fibril

The cross-β amyloid form of peptides and proteins represents an archetypal and widely accessible structure consisting of ordered arrays of β-sheet filaments. These complex aggregates have remarkable chemical and physical properties, and the conversion of normally soluble functional forms of proteins into amyloid structures is linked to many debilitating human diseases, including several common forms of age-related dementia. Despite their importance, however, cross-β amyloid fibrils have proved to be recalcitrant to detailed structural analysis. By combining structural constraints from a series of experimental techniques spanning five orders of magnitude in length scale—including magic angle spinning nuclear magnetic resonance spectroscopy, X-ray fiber diffraction, cryoelectron microscopy, scanning transmission electron microscopy, and atomic force microscopy—we report the atomic-resolution (0.5 Å) structures of three amyloid polymorphs formed by an 11-residue peptide. These structures reveal the details of the packing interactions by which the constituent β-strands are assembled hierarchically into protofilaments, filaments, and mature fibrils.

[1]  Michele Vendruscolo,et al.  Role of Intermolecular Forces in Defining Material Properties of Protein Nanofibrils , 2007, Science.

[2]  Nikolaus M. Szeverenyi,et al.  Observation of spin exchange by two-dimensional fourier transform 13C cross polarization-magic-angle spinning , 1982 .

[3]  Adam Douglass,et al.  Mechanism of Prion Propagation: Amyloid Growth Occurs by Monomer Addition , 2004, PLoS biology.

[4]  C. Dobson,et al.  Protein misfolding, functional amyloid, and human disease. , 2006, Annual review of biochemistry.

[5]  Christopher M. Dobson,et al.  The protofilament structure of insulin amyloid fibrils , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[7]  Glyn L. Devlin,et al.  Functionalised amyloid fibrils for roles in cell adhesion. , 2008, Biomaterials.

[8]  R. Griffin,et al.  Band-selective carbonyl to aliphatic side chain 13C-13C distance measurements in U-13C,15N-labeled solid peptides by magic angle spinning NMR. , 2004, Journal of the American Chemical Society.

[9]  Ehud Gazit,et al.  A possible role for π‐stacking in the self‐assembly of amyloid fibrils , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  David Eisenberg,et al.  Atomic structures of amyloid cross-beta spines reveal varied steric zippers. , 2007, Nature.

[11]  C. Dobson,et al.  Intermolecular structure determination of amyloid fibrils with magic-angle spinning and dynamic nuclear polarization NMR. , 2011, Journal of the American Chemical Society.

[12]  Elena Orlova,et al.  Cryo‐electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing , 1999, The EMBO journal.

[13]  L. Serpell,et al.  Common core structure of amyloid fibrils by synchrotron X-ray diffraction. , 1997, Journal of molecular biology.

[14]  S. Müller,et al.  Studies on the in vitro assembly of a beta 1-40: implications for the search for a beta fibril formation inhibitors. , 2000, Journal of structural biology.

[15]  Kenneth H Downing,et al.  Structural basis of interprotofilament interaction and lateral deformation of microtubules. , 2010, Structure.

[16]  Beat H. Meier,et al.  Amyloid Fibrils of the HET-s(218–289) Prion Form a β Solenoid with a Triangular Hydrophobic Core , 2008, Science.

[17]  John Collinge,et al.  A General Model of Prion Strains and Their Pathogenicity , 2007, Science.

[18]  S. Müller,et al.  Studies on the in Vitro Assembly of Aβ 1–40: Implications for the Search for Aβ Fibril Formation Inhibitors , 2000 .

[19]  Christopher M Dobson,et al.  The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation , 2002, The EMBO journal.

[20]  Atanas V Koulov,et al.  Functional amyloid--from bacteria to humans. , 2007, Trends in biochemical sciences.

[21]  S. Ludtke,et al.  Interprotofilament interactions between Alzheimer's Aβ1–42 peptides in amyloid fibrils revealed by cryoEM , 2009, Proceedings of the National Academy of Sciences.

[22]  E. Orlova,et al.  Structural Analysis of Macromolecular Assemblies by Electron Microscopy , 2011, Chemical reviews.

[23]  C. Dobson.  Protein misfolding, evolution and disease. , 1999, Trends in biochemical sciences.

[24]  Richard D. Leapman,et al.  Self-Propagating, Molecular-Level Polymorphism in Alzheimer's ß-Amyloid Fibrils , 2005, Science.

[25]  Robert A. Grothe,et al.  Structure of the cross-beta spine of amyloid-like fibrils. , 2005, Nature.

[26]  Michele Vendruscolo,et al.  Metastability of native proteins and the phenomenon of amyloid formation. , 2011, Journal of the American Chemical Society.

[27]  C. Jaroniec,et al.  3D TEDOR NMR experiments for the simultaneous measurement of multiple carbon-nitrogen distances in uniformly (13)C,(15)N-labeled solids. , 2002, Journal of the American Chemical Society.

[28]  C. Dobson,et al.  Protein solubility and protein homeostasis: a generic view of protein misfolding disorders. , 2011, Cold Spring Harbor perspectives in biology.

[29]  M. Engelhard,et al.  Structural characterization of polyglutamine fibrils by solid-state NMR spectroscopy. , 2011, Journal of molecular biology.

[30]  R. Wetzel,et al.  The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils. , 2011, Journal of the American Chemical Society.

[31]  R. Riek,et al.  3D structure of Alzheimer's amyloid-β(1–42) fibrils , 2005 .

[32]  Tuomas P. J. Knowles,et al.  An Analytical Solution to the Kinetics of Breakable Filament Assembly , 2009, Science.

[33]  C. Dobson,et al.  High-resolution molecular structure of a peptide in an amyloid fibril determined by magic angle spinning NMR spectroscopy. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Christopher M Dobson,et al.  Spatial persistence of angular correlations in amyloid fibrils. , 2006, Physical review letters.

[35]  N. Grigorieff,et al.  Comparison of Alzheimer Aβ(1–40) and Aβ(1–42) amyloid fibrils reveals similar protofilament structures , 2009, Proceedings of the National Academy of Sciences.

[36]  K. Sharp,et al.  Intrinsic Linear Heterogeneity of Amyloid β Protein Fibrils Revealed by Higher Resolution Mass-per-length Determinations* , 2010, The Journal of Biological Chemistry.

[37]  Anthony W. Fitzpatrick,et al.  Inversion of the Balance between Hydrophobic and Hydrogen Bonding Interactions in Protein Folding and Aggregation , 2011, PLoS Comput. Biol..

[38]  R. Riek,et al.  3D structure of Alzheimer's amyloid-beta(1-42) fibrils. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Mathias Jucker,et al.  The Amyloid State of Proteins in Human Diseases , 2012, Cell.

[40]  Andreas Bracher,et al.  Molecular chaperones in protein folding and proteostasis , 2011, Nature.

[41]  T. Gullion,et al.  Rotational-Echo, Double-Resonance NMR , 1989 .

[42]  A. Donald,et al.  The binding of thioflavin-T to amyloid fibrils: localisation and implications. , 2005, Journal of structural biology.

[43]  Heather T. McFarlane,et al.  Atomic structures of amyloid cross-β spines reveal varied steric zippers , 2007, Nature.

[44]  R. Leapman,et al.  A structural model for Alzheimer's β-amyloid fibrils based on experimental constraints from solid state NMR , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[45]  U Aebi,et al.  Polymorphic fibrillar assembly of human amylin. , 1997, Journal of structural biology.

[46]  N. Grigorieff,et al.  Paired β-sheet structure of an Aβ(1-40) amyloid fibril revealed by electron microscopy , 2008, Proceedings of the National Academy of Sciences.