Cross-beta Order and Diversity in Nanocrystals of an Amyloid-forming Peptide

Díaz-Avalos, Rubén; Long, Chris; Fontano, Eric; Balbirnie, Melinda; Grothe, Robert; Eisenberg, David; Caspar, D. L. D.

doi:10.1016/s0022-2836(03)00659-4

Cited by 99 publications

(115 citation statements)

References 21 publications

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“…Hydration apparently affects molecular motions, but not structure. These conclusions from solid state NMR spectra may be related to the work of Diaz-Avalos et al, in which diffraction measurements on a seven-residue, glutamine-and asparagine-rich peptide in an amyloid-like nanocrystalline form revealed a low density of water, attributed to sidechain hydrogen bonding (88).…”

Section: Effects Of Hydration On Solid State Nmr Spectra Argue Againsmentioning

confidence: 68%

Parallel β-Sheets and Polar Zippers in Amyloid Fibrils Formed by Residues 10−39 of the Yeast Prion Protein Ure2p

et al. 2005

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We report the results of solid state nuclear magnetic resonance (NMR) and atomic force microscopy measurements on amyloid fibrils formed by residues 10-39 of the yeast prion protein Ure2p (Ure2p ). Measurements of intermolecular 13 C-13 C nuclear magnetic dipole-dipole couplings indicate that Ure2p 10-39 fibrils contain in-register parallel β-sheets. Measurements of intermolecular 15 N-13 C dipole-dipole couplings, using a new solid state NMR technique called DSQ-REDOR, are consistent with hydrogen bonds between sidechain amide groups of Gln18 residues. Such sidechain hydrogen bonding interactions have been called "polar zippers" by M.F. Perutz and have been proposed to stabilize amyloid fibrils formed by peptides with glutamine-and asparaginerich sequences, such as Ure2p . We propose that polar zipper interactions account for the inregister parallel β-sheet structure in Ure2p 10-39 fibrils and that similar peptides will also exhibit parallel β-sheet structures in amyloid fibrils. We present molecular models for Ure2p fibrils that are consistent with available experimental data. Finally, we show that solid state 13 C NMR chemical shifts for 13 C-labeled Ure2p 10-39 fibrils are insensitive to hydration level, indicating that the fibril structure is not affected by the presence or absence of bulk water. AbbreviationsNMR, nuclear magnetic resonance; Aβ, β-amyloid peptide; Ure2p 10-39 , residues 10-39 of the Ure2p yeast prion protein; EM, electron microscopy; FMOC, 9-fluorenylmethoxycarbonyl; TFA, trifluoroacetic acid; AFM, atomic force microscopy; MAS, magic-angle spinning; fpRFDR-CT, constant-time finite-pulse radiofrequency-driven recoupling; REDOR, rotational echo double resonance; DSQ, double single-quantum; TPPM, two-pulse phase modulation; CSA, chemical shift anisotropy; MD, molecular dynamics One goal of current efforts to elucidate the molecular structures of amyloid fibrils (1-35) is to identify the intermolecular interactions that determine the details of these structures and make amyloid fibrils a stable structural state for many peptides and proteins despite their diversity of amino acid sequences (36)(37)(38)(39)(40)(41). Recent studies by solid state nuclear magnetic resonance (NMR) of fibrils formed by the β-amyloid (Aβ) peptide associated with Alzheimer's disease (5,13,16,18,24,30,31), by various Aβ fragments (1,3,4,(6)(7)(8)12,21,25), and by other amyloidforming peptides (22) indicate that the β-sheets in amyloid fibrils have structures that tend to maximize contacts among hydrophobic residues when the component peptides contain continuous hydrophobic segments. Electrostatic interactions appear to play a secondary role, dictating the choice between parallel and antiparallel β-sheet structures when either type of structure could maximize hydrophobic contacts (6,21,23) and dictating the precise registry of *corresponding author: Dr. Robert Tycko, National Institutes of Health, Building 5, Room 112, Bethesda, MD 20892-0520. phone 301-402-8272, fax 301-496-0825, e-mailrobertty@mail.nih -sh...

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Section: Effects Of Hydration On Solid State Nmr Spectra Argue Againsmentioning

confidence: 68%

Parallel β-Sheets and Polar Zippers in Amyloid Fibrils Formed by Residues 10−39 of the Yeast Prion Protein Ure2p

et al. 2005

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“…In our model, extended sheets spiral about the fibril axis, tilting away from the axis at Ϸ45°, and may represent intermediates en route to the fibrillar state, as expected for protofibrils. In fact, recent attempts to model fibrils with hydrogen-bonding patterns parallel to the fiber axis by using ␤-sheets perpendicular to the fiber axis poorly reproduce the experimental constraints, which suggests that other models may be necessary for fibrils as well (61).…”

Section: Resultsmentioning

confidence: 99%

From conversion to aggregation: Protofibril formation of the prion protein

DeMarco

Daggett

2004

Proc. Natl. Acad. Sci. U.S.A.

294

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The ability to diagnose and treat prion diseases is limited by our current understanding of the conversion process of the protein from healthy to harmful isoform. Whereas the monomeric, benign species is well characterized, the misfolded conformations responsible for infectivity and neurodegeneration remain elusive. There is mounting evidence that fibrillization intermediates, or protofibrils, but not mature fibrils or plaques, are the pathogenic species in amyloid diseases. Here, we use molecular dynamics to simulate the conversion of the prion protein. Molecular dynamics simulation produces a scrapie prion protein-like conformation enriched in ␤-structure that is in good agreement with available experimental data. The converted conformation was then used to model a protofibril by means of the docking of hydrophobic patches of the template structure to form hydrogen-bonded sheets spanning adjacent subunits. The resulting protofibril model provides a nonbranching aggregate with a 31 axis of symmetry that is in good agreement with a wide variety of experimental data; importantly, it was derived from realistic simulation of the conversion process.

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“…The fibers are thought to be composed of two or more ␤-sheets held together by hydrophobic surface contacts or specific electrostatic interactions. Nanocrystals of a polypeptide have yielded some additional information concerning the arrangement of the ␤-strands within an amyloid-forming polypeptide (7). However, the exact conformation remains unknown.…”

mentioning

confidence: 99%

Molecular basis for amyloid fibril formation and stability

Makin

Atkins²,

Sikorski³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

622

586

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The molecular structure of the amyloid fibril has remained elusive because of the difficulty of growing well diffracting crystals. By using a sequence-designed polypeptide, we have produced crystals of an amyloid fiber. These crystals diffract to high resolution (1 Å) by electron and x-ray diffraction, enabling us to determine a detailed structure for amyloid. The structure reveals that the polypeptides form fibrous crystals composed of antiparallel ␤-sheets in a cross-␤ arrangement, characteristic of all amyloid fibers, and allows us to determine the side-chain packing within an amyloid fiber. The antiparallel ␤-sheets are zipped together by means of -bonding between adjacent phenylalanine rings and salt-bridges between charge pairs (glutamic acid-lysine), thus controlling and stabilizing the structure. These interactions are likely to be important in the formation and stability of other amyloid fibrils.x-ray diffraction ͉ side-chain packing ͉ structure ͉ -bonding ͉ ␤-sheet interaction

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Cross-beta Order and Diversity in Nanocrystals of an Amyloid-forming Peptide

Cited by 99 publications

References 21 publications

Parallel β-Sheets and Polar Zippers in Amyloid Fibrils Formed by Residues 10−39 of the Yeast Prion Protein Ure2p

Parallel β-Sheets and Polar Zippers in Amyloid Fibrils Formed by Residues 10−39 of the Yeast Prion Protein Ure2p

From conversion to aggregation: Protofibril formation of the prion protein

Molecular basis for amyloid fibril formation and stability

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