We present a structural model for amyloid fibrils formed by the 40-residue ␤-amyloid peptide associated with Alzheimer's disease (A␤ 1-40), based on a set of experimental constraints from solid state NMR spectroscopy. The model additionally incorporates the cross-␤ structural motif established by x-ray fiber diffraction and satisfies constraints on A␤ 1-40 fibril dimensions and mass-per-length determined from electron microscopy. Approximately the first 10 residues of A␤ 1-40 are structurally disordered in the fibrils. Residues 12-24 and 30 -40 adopt ␤-strand conformations and form parallel ␤-sheets through intermolecular hydrogen bonding. Residues 25-29 contain a bend of the peptide backbone that brings the two ␤-sheets in contact through sidechain-sidechain interactions. A single cross-␤ unit is then a double-layered ␤-sheet structure with a hydrophobic core and one hydrophobic face. The only charged sidechains in the core are those of D23 and K28, which form salt bridges. Fibrils with minimum mass-per-length and diameter consist of two cross-␤ units with their hydrophobic faces juxtaposed.A myloid fibrils are filamentous structures, with typical diameters of Ϸ10 nm and lengths up to several micrometers, formed by numerous peptides and proteins with disparate sequences and molecular weights. Biomedical interest in amyloid fibrils arises from their occurrence in amyloid diseases (1), including Alzheimer's disease, type 2 diabetes, Huntington's disease, and prion diseases. Current interest in the molecular structures of amyloid fibrils additionally arises from fundamental questions regarding the molecular mechanism of amyloid formation and the nature of the intermolecular interactions that stabilize these structures for an extremely diverse class of polypeptides.No high-resolution molecular structure of an amyloid fibril has yet been determined experimentally because amyloid fibrils are noncrystalline solid materials and are therefore incompatible with x-ray crystallography and liquid state NMR. X-ray fiber diffraction shows that amyloid fibrils contain cross-␤ structural motifs, i.e., extended ␤-sheets in which the ␤-strand segments run approximately perpendicular to, and the intermolecular hydrogen bonds run approximately parallel to, the long axis of the fibril (2, 3). Other molecular-level structural features of amyloid fibrils are not well established.In the case of fibrils formed by the full-length ␤-amyloid peptide associated with Alzheimer's disease (A␤), which ranges from 39 to 43 residues in length in vivo (4, 5), several molecular models have been proposed (6-10). These models exhibit many qualitative and quantitative differences, reflecting the paucity of experimental constraints. All of these models are inconsistent with recent measurements of 13 C-13 C nuclear magnetic dipole-dipole couplings (i.e., intermolecular distances) by solid state NMR (11-13), which imply an in-register parallel alignment of peptide chains within the cross-␤ motif in A␤ 1-40 and A␤ 1-42 fibrils (A␤ mϪn denotes residues m t...

Eukaryotic cells contain assemblies of RNAs and proteins termed RNA granules. Many proteins within these bodies contain KH or RRM RNA-binding domains as well as low complexity (LC) sequences of unknown function. We discovered that exposure of cell or tissue lysates to a biotinylated isoxazole (b-isox) chemical precipitated hundreds of RNA-binding proteins with significant overlap to the constituents of RNA granules. The LC sequences within these proteins are both necessary and sufficient for b-isox-mediated aggregation, and these domains can undergo a concentration-dependent phase transition to a hydrogel-like state in the absence of the chemical. X-ray diffraction and EM studies revealed the hydrogels to be composed of uniformly polymerized amyloid-like fibers. Unlike pathogenic fibers, the LC sequence-based polymers described here are dynamic and accommodate heterotypic polymerization. These observations offer a framework for understanding the function of LC sequences as well as an organizing principle for cellular structures that are not membrane bound.