A New Structural Model of Aβ₄₀ Fibrils

Abstract

The amyloid fibrils of beta-amyloid (Aβ) peptides play important roles in the pathology of Alzheimer's disease. Comprehensive solid-state NMR (SSNMR) structural studies on uniformly isotope-labeled Aβ assemblies have been hampered for a long time by sample heterogeneity and low spectral resolution. In this work, SSNMR studies on well-ordered fibril samples of Aβ(40) with an additional N-terminal methionine provide high-resolution spectra which lead to an accurate structural model. The fibrils studied here carry distinct structural features compared to previous reports. The inter-β-strand contacts within the U-shaped β-strand-turn-β-strand motif are shifted, the N-terminal region adopts a β-conformation, and new inter-monomer contacts occur at the protofilament interface. The revealed structural diversity in Aβ fibrils points to a complex picture of Aβ fibrillation.

β-Helical architecture of cytoskeletal bactofilin filaments revealed by solid-state NMR

“…This is in large part due to the spontaneous formation, inertness, and insolubility of bactofilin polymers, which makes them difficult substrates for crystallography studies as well as conventional liquid-state NMR methods. We therefore resorted to the use of solid-state NMR (ssNMR) spectroscopy, a technique that has recently been adapted to obtain high-resolution structural information on insoluble and noncrystalline protein assemblies, including functional oligomeric assemblies (15)(16)(17), disease-related amyloid fibrils (18)(19)(20)(21), and membrane proteins in a lipid bilayer environment (22)(23)(24)(25)(26). In this study, we have applied state-of-theart magic-angle spinning ssNMR spectroscopy in combination with a range of other biophysical methods to filaments of the C. crescentus bactofilin BacA (161 residues).…”

Coexistence of ribbon and helical fibrils originating from hIAPP 20–29 revealed by quantitative nanomechanical atomic force microscopy

“…High-resolution solidstate NMR structures of hIAPP 20-29 fibrils have provided detailed insight into the antiparallel hetero zipper with a twist along the fibril axis (21-23). However, no uniform detailed theory of the self-assembly behavior is available (11) and, in particular, the transitions between different intermediates during fibrillation remain to be elucidated.Here, we apply high-resolution AFM and the recently developed microsecond force spectroscopy (μFS) for quantitative nanomechanical maps (24, 25) to explore the nanostructures and nanomechanical properties of species formed during the self-assembly of the decapeptide hIAPP [20][21][22][23][24][25][26][27][28][29] . By following the temporal evolution of the amyloid peptide self-assembly process, we calculate the average thickening speed of ribbon structures, which is considered a key intermediate in the ribbon-like packing scheme (26,27).…”

“…hIAPP is a 37-amino-acid peptide hormone, and the decapeptide SNNFGAILSS comprising hIAPP [20][21][22][23][24][25][26][27][28][29] , considered to be the core fibrillating element of hIAPP relating to T2D (18, 19), is critical for the fibrillation of hIAPP and shows cytotoxicity (19). The analysis of hIAPP 20-29 fibrils revealed two distinct fibril types, comprising either parallel β-strands or antiparallel β-strands (20).…”

“…Transitions among the various intermediate stages are the subject of many studies but are not yet fully elucidated. Here, we combine high-resolution atomic force microscopy and quantitative nanomechanical mapping to determine the self-assembled structures of the decapeptide hIAPP [20][21][22][23][24][25][26][27][28][29] , which is considered to be the fibrillating core fragment of the human islet amyloid polypeptide (hIAPP) involved in type-2 diabetes. We successfully follow the evolution of hIAPP [20][21][22][23][24][25][26][27][28][29] nanostructures over time, calculate the average thickening speed of small ribbon-like structures, and provide evidence of the coexistence of ribbon and helical fibrils, highlighting a key step within the self-assembly model.…”

Hydrogen bonding involving side chain exchangeable groups stabilizes amyloid quarternary structure

“…4 In the past, several Ab fibril structure models have been suggested. These are based on MAS solidstate NMR experiments, [5][6][7][8][9][10][11] and cryo-electron microscopic image reconstructions. 12 Even though there is some controversy concerning the conformational space that Ab fibrils can adopt, all published models, including the 2-fold 7,10 and 3-fold 9 symmetric Ab 1-40 fibril structure suggested by Tycko, and Bertini and co-workers, agree on the basic building block which involves a b-sheet (b1, residues 12-24), a turn, and a second b-sheet (b2, residues [28][29][30][31][32][33][34][35][36][37][38][39][40].…”