Skip to main content
PMC home page
Biophysical Journal logoLink to Biophysical Journal
. 2002 Aug;83(2):1205–1216. doi: 10.1016/S0006-3495(02)75244-2

Supramolecular structure in full-length Alzheimer's beta-amyloid fibrils: evidence for a parallel beta-sheet organization from solid-state nuclear magnetic resonance.

John J Balbach 1, Aneta T Petkova 1, Nathan A Oyler 1, Oleg N Antzutkin 1, David J Gordon 1, Stephen C Meredith 1, Robert Tycko 1
PMCID: PMC1302222  PMID: 12124300

Abstract

We report constraints on the supramolecular structure of amyloid fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (A beta(1-40)) obtained from solid-state nuclear magnetic resonance (NMR) measurements of intermolecular dipole-dipole couplings between (13)C labels at 11 carbon sites in residues 2 through 39. The measurements are carried out under magic-angle spinning conditions, using the constant-time finite-pulse radiofrequency-driven recoupling (fpRFDR-CT) technique. We also present one-dimensional (13)C magic-angle spinning NMR spectra of the labeled A beta(1-40) samples. The fpRFDR-CT data reveal nearest-neighbor intermolecular distances of 4.8 +/- 0.5 A for carbon sites from residues 12 through 39, indicating a parallel alignment of neighboring peptide chains in the predominantly beta-sheet structure of the amyloid fibrils. The one-dimensional NMR spectra indicate structural order at these sites. The fpRFDR-CT data and NMR spectra also indicate structural disorder in the N-terminal segment of A beta(1-40), including the first nine residues. These results place strong constraints on any molecular-level structural model for full-length beta-amyloid fibrils.

Full Text

The Full Text of this article is available as a PDF (172.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antzutkin O. N., Balbach J. J., Leapman R. D., Rizzo N. W., Reed J., Tycko R. Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of beta-sheets in Alzheimer's beta-amyloid fibrils. Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13045–13050. doi: 10.1073/pnas.230315097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Balbach J. J., Ishii Y., Antzutkin O. N., Leapman R. D., Rizzo N. W., Dyda F., Reed J., Tycko R. Amyloid fibril formation by A beta 16-22, a seven-residue fragment of the Alzheimer's beta-amyloid peptide, and structural characterization by solid state NMR. Biochemistry. 2000 Nov 14;39(45):13748–13759. doi: 10.1021/bi0011330. [DOI] [PubMed] [Google Scholar]
  3. Benzinger T. L., Gregory D. M., Burkoth T. S., Miller-Auer H., Lynn D. G., Botto R. E., Meredith S. C. Propagating structure of Alzheimer's beta-amyloid(10-35) is parallel beta-sheet with residues in exact register. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13407–13412. doi: 10.1073/pnas.95.23.13407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benzinger T. L., Gregory D. M., Burkoth T. S., Miller-Auer H., Lynn D. G., Botto R. E., Meredith S. C. Two-dimensional structure of beta-amyloid(10-35) fibrils. Biochemistry. 2000 Mar 28;39(12):3491–3499. doi: 10.1021/bi991527v. [DOI] [PubMed] [Google Scholar]
  5. Blackley H. K., Sanders G. H., Davies M. C., Roberts C. J., Tendler S. J., Wilkinson M. J. In-situ atomic force microscopy study of beta-amyloid fibrillization. J Mol Biol. 2000 May 19;298(5):833–840. doi: 10.1006/jmbi.2000.3711. [DOI] [PubMed] [Google Scholar]
  6. Blake C., Serpell L. Synchrotron X-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous beta-sheet helix. Structure. 1996 Aug 15;4(8):989–998. doi: 10.1016/s0969-2126(96)00104-9. [DOI] [PubMed] [Google Scholar]
  7. Chaney M. O., Webster S. D., Kuo Y. M., Roher A. E. Molecular modeling of the Abeta1-42 peptide from Alzheimer's disease. Protein Eng. 1998 Sep;11(9):761–767. doi: 10.1093/protein/11.9.761. [DOI] [PubMed] [Google Scholar]
  8. Chiti F., Webster P., Taddei N., Clark A., Stefani M., Ramponi G., Dobson C. M. Designing conditions for in vitro formation of amyloid protofilaments and fibrils. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3590–3594. doi: 10.1073/pnas.96.7.3590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Conway K. A., Harper J. D., Lansbury P. T., Jr Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid. Biochemistry. 2000 Mar 14;39(10):2552–2563. doi: 10.1021/bi991447r. [DOI] [PubMed] [Google Scholar]
  10. Emsley P., Charles I. G., Fairweather N. F., Isaacs N. W. Structure of Bordetella pertussis virulence factor P.69 pertactin. Nature. 1996 May 2;381(6577):90–92. doi: 10.1038/381090a0. [DOI] [PubMed] [Google Scholar]
  11. Fraser P. E., Nguyen J. T., Inouye H., Surewicz W. K., Selkoe D. J., Podlisny M. B., Kirschner D. A. Fibril formation by primate, rodent, and Dutch-hemorrhagic analogues of Alzheimer amyloid beta-protein. Biochemistry. 1992 Nov 10;31(44):10716–10723. doi: 10.1021/bi00159a011. [DOI] [PubMed] [Google Scholar]
  12. Fraser P. E., Nguyen J. T., Surewicz W. K., Kirschner D. A. pH-dependent structural transitions of Alzheimer amyloid peptides. Biophys J. 1991 Nov;60(5):1190–1201. doi: 10.1016/S0006-3495(91)82154-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. George A. R., Howlett D. R. Computationally derived structural models of the beta-amyloid found in Alzheimer's disease plaques and the interaction with possible aggregation inhibitors. Biopolymers. 1999 Dec;50(7):733–741. doi: 10.1002/(SICI)1097-0282(199912)50:7<733::AID-BIP6>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  14. Goldsbury C. S., Wirtz S., Müller S. A., Sunderji S., Wicki P., Aebi U., Frey P. Studies on the in vitro assembly of a beta 1-40: implications for the search for a beta fibril formation inhibitors. J Struct Biol. 2000 Jun;130(2-3):217–231. doi: 10.1006/jsbi.2000.4259. [DOI] [PubMed] [Google Scholar]
  15. Goldsbury C., Kistler J., Aebi U., Arvinte T., Cooper G. J. Watching amyloid fibrils grow by time-lapse atomic force microscopy. J Mol Biol. 1999 Jan 8;285(1):33–39. doi: 10.1006/jmbi.1998.2299. [DOI] [PubMed] [Google Scholar]
  16. Gregory D. M., Benzinger T. L., Burkoth T. S., Miller-Auer H., Lynn D. G., Meredith S. C., Botto R. E. Dipolar recoupling NMR of biomolecular self-assemblies: determining inter- and intrastrand distances in fibrilized Alzheimer's beta-amyloid peptide. Solid State Nucl Magn Reson. 1998 Dec;13(3):149–166. doi: 10.1016/s0926-2040(98)00086-1. [DOI] [PubMed] [Google Scholar]
  17. Griffin R. G. Dipolar recoupling in MAS spectra of biological solids. Nat Struct Biol. 1998 Jul;5 (Suppl):508–512. doi: 10.1038/749. [DOI] [PubMed] [Google Scholar]
  18. Harper J. D., Lieber C. M., Lansbury P. T., Jr Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer's disease amyloid-beta protein. Chem Biol. 1997 Dec;4(12):951–959. doi: 10.1016/s1074-5521(97)90303-3. [DOI] [PubMed] [Google Scholar]
  19. Harper J. D., Wong S. S., Lieber C. M., Lansbury P. T., Jr Assembly of A beta amyloid protofibrils: an in vitro model for a possible early event in Alzheimer's disease. Biochemistry. 1999 Jul 13;38(28):8972–8980. doi: 10.1021/bi9904149. [DOI] [PubMed] [Google Scholar]
  20. Hilbich C., Kisters-Woike B., Reed J., Masters C. L., Beyreuther K. Aggregation and secondary structure of synthetic amyloid beta A4 peptides of Alzheimer's disease. J Mol Biol. 1991 Mar 5;218(1):149–163. doi: 10.1016/0022-2836(91)90881-6. [DOI] [PubMed] [Google Scholar]
  21. Inouye H., Fraser P. E., Kirschner D. A. Structure of beta-crystallite assemblies formed by Alzheimer beta-amyloid protein analogues: analysis by x-ray diffraction. Biophys J. 1993 Feb;64(2):502–519. doi: 10.1016/S0006-3495(93)81393-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ishii Y., Yesinowski J. P., Tycko R. Sensitivity enhancement in solid-state (13)C NMR of synthetic polymers and biopolymers by (1)H NMR detection with high-speed magic angle spinning. J Am Chem Soc. 2001 Mar 28;123(12):2921–2922. doi: 10.1021/ja015505j. [DOI] [PubMed] [Google Scholar]
  23. Jiménez J. L., Guijarro J. I., Orlova E., Zurdo J., Dobson C. M., Sunde M., Saibil H. R. Cryo-electron microscopy structure of an SH3 amyloid fibril and model of the molecular packing. EMBO J. 1999 Feb 15;18(4):815–821. doi: 10.1093/emboj/18.4.815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kheterpal I., Williams A., Murphy C., Bledsoe B., Wetzel R. Structural features of the Abeta amyloid fibril elucidated by limited proteolysis. Biochemistry. 2001 Oct 2;40(39):11757–11767. doi: 10.1021/bi010805z. [DOI] [PubMed] [Google Scholar]
  25. Kheterpal I., Zhou S., Cook K. D., Wetzel R. Abeta amyloid fibrils possess a core structure highly resistant to hydrogen exchange. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13597–13601. doi: 10.1073/pnas.250288897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Khurana R., Fink A. L. Do parallel beta-helix proteins have a unique fourier transform infrared spectrum? Biophys J. 2000 Feb;78(2):994–1000. doi: 10.1016/S0006-3495(00)76657-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lansbury P. T., Jr, Costa P. R., Griffiths J. M., Simon E. J., Auger M., Halverson K. J., Kocisko D. A., Hendsch Z. S., Ashburn T. T., Spencer R. G. Structural model for the beta-amyloid fibril based on interstrand alignment of an antiparallel-sheet comprising a C-terminal peptide. Nat Struct Biol. 1995 Nov;2(11):990–998. doi: 10.1038/nsb1195-990. [DOI] [PubMed] [Google Scholar]
  28. Lazo N. D., Downing D. T. Amyloid fibrils may be assembled from beta-helical protofibrils. Biochemistry. 1998 Feb 17;37(7):1731–1735. doi: 10.1021/bi971016d. [DOI] [PubMed] [Google Scholar]
  29. Li L., Darden T. A., Bartolotti L., Kominos D., Pedersen L. G. An atomic model for the pleated beta-sheet structure of Abeta amyloid protofilaments. Biophys J. 1999 Jun;76(6):2871–2878. doi: 10.1016/S0006-3495(99)77442-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Malinchik S. B., Inouye H., Szumowski K. E., Kirschner D. A. Structural analysis of Alzheimer's beta(1-40) amyloid: protofilament assembly of tubular fibrils. Biophys J. 1998 Jan;74(1):537–545. doi: 10.1016/S0006-3495(98)77812-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Petkova Aneta T., Tycko Robert. Sensitivity enhancement in structural measurements by solid state NMR through pulsed spin locking. J Magn Reson. 2002 Apr;155(2):293–299. doi: 10.1006/jmre.2002.2519. [DOI] [PubMed] [Google Scholar]
  32. Roher A. E., Lowenson J. D., Clarke S., Wolkow C., Wang R., Cotter R. J., Reardon I. M., Zürcher-Neely H. A., Heinrikson R. L., Ball M. J. Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease. J Biol Chem. 1993 Feb 15;268(5):3072–3083. [PubMed] [Google Scholar]
  33. Serpell L. C., Blake C. C., Fraser P. E. Molecular structure of a fibrillar Alzheimer's A beta fragment. Biochemistry. 2000 Oct 31;39(43):13269–13275. doi: 10.1021/bi000637v. [DOI] [PubMed] [Google Scholar]
  34. Serpell L. C., Smith J. M. Direct visualisation of the beta-sheet structure of synthetic Alzheimer's amyloid. J Mol Biol. 2000 May 26;299(1):225–231. doi: 10.1006/jmbi.2000.3650. [DOI] [PubMed] [Google Scholar]
  35. Stine W. B., Jr, Snyder S. W., Ladror U. S., Wade W. S., Miller M. F., Perun T. J., Holzman T. F., Krafft G. A. The nanometer-scale structure of amyloid-beta visualized by atomic force microscopy. J Protein Chem. 1996 Feb;15(2):193–203. doi: 10.1007/BF01887400. [DOI] [PubMed] [Google Scholar]
  36. Storey E., Cappai R. The amyloid precursor protein of Alzheimer's disease and the Abeta peptide. Neuropathol Appl Neurobiol. 1999 Apr;25(2):81–97. doi: 10.1046/j.1365-2990.1999.00164.x. [DOI] [PubMed] [Google Scholar]
  37. Sunde M., Blake C. C. From the globular to the fibrous state: protein structure and structural conversion in amyloid formation. Q Rev Biophys. 1998 Feb;31(1):1–39. doi: 10.1017/s0033583598003400. [DOI] [PubMed] [Google Scholar]
  38. Sunde M., Serpell L. C., Bartlam M., Fraser P. E., Pepys M. B., Blake C. C. Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J Mol Biol. 1997 Oct 31;273(3):729–739. doi: 10.1006/jmbi.1997.1348. [DOI] [PubMed] [Google Scholar]
  39. Tjernberg L. O., Callaway D. J., Tjernberg A., Hahne S., Lilliehök C., Terenius L., Thyberg J., Nordstedt C. A molecular model of Alzheimer amyloid beta-peptide fibril formation. J Biol Chem. 1999 Apr 30;274(18):12619–12625. doi: 10.1074/jbc.274.18.12619. [DOI] [PubMed] [Google Scholar]
  40. Tycko R. Biomolecular solid state NMR: advances in structural methodology and applications to peptide and protein fibrils. Annu Rev Phys Chem. 2001;52:575–606. doi: 10.1146/annurev.physchem.52.1.575. [DOI] [PubMed] [Google Scholar]
  41. Tycko R. Solid-state NMR as a probe of amyloid fibril structure. Curr Opin Chem Biol. 2000 Oct;4(5):500–506. doi: 10.1016/s1367-5931(00)00123-x. [DOI] [PubMed] [Google Scholar]
  42. Tycko R. Solid-state nuclear magnetic resonance techniques for structural studies of amyloid fibrils. Methods Enzymol. 2001;339:390–413. doi: 10.1016/s0076-6879(01)39324-2. [DOI] [PubMed] [Google Scholar]
  43. Weliky D. P., Bennett A. E., Zvi A., Anglister J., Steinbach P. J., Tycko R. Solid-state NMR evidence for an antibody-dependent conformation of the V3 loop of HIV-1 gp120. Nat Struct Biol. 1999 Feb;6(2):141–145. doi: 10.1038/5827. [DOI] [PubMed] [Google Scholar]
  44. Yoder M. D., Keen N. T., Jurnak F. New domain motif: the structure of pectate lyase C, a secreted plant virulence factor. Science. 1993 Jun 4;260(5113):1503–1507. doi: 10.1126/science.8502994. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES

  NODES
twitter 2