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Cited by 334

The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments.

Schweers, O, Mandelkow, E M, Biernat, J, Mandelkow, E·1995·Proceedings of the National Academy of Sciences

Abstract

One of the hallmarks of Alzheimer disease is the pathological aggregation of tau protein into paired helical filaments (PHFs) and neurofibrillary tangles. Here we describe the in vitro assembly of recombinant tau protein and constructs derived from it into PHFs. Though whole tau assembled poorly, constructs containing three internal repeats (corresponding to the fetal tau isoform) formed PHFs reproducibly. This ability depended on intermolecular disulfide bridges formed by the single Cys-322. Blocking the SH group, mutating Cys for Ala, or keeping tau in a reducing environment all inhibited assembly. With constructs derived from four-repeat tau (having the additional repeat no. 2 and a second Cys-291), PHF assembly was blocked because Cys-291 and Cys-322 interact within the molecule. PHF assembly was enabled again by mutating Cys-291 for Ala. The synthetic PHFs bound the dye thioflavin S used in Alzheimer disease diagnostics. The data imply that the redox potential in the neuron is crucial for PHF assembly, independently or in addition to pathological phosphorylation reactions.

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  1. [3]Kirschner, D. A., Abraham, C. & Selkoe, D. J. (1986) Proc. Natl. Acad. Sci. USA 83, 503–507.
  2. [13]Shearman, M. S., Ragan, C. I. & Iversen, L. L. (1994) Proc. Natl. Acad. Sci. USA 91, 1470–1474.
  3. [12]Smith, C. D., Carney, J. M., Starke-Reed, P. E., Oliver, C. N., Stadtman, E. R., Floyd, R. A. & Markesbery, W. R. (1991) Proc. Natl. Acad. Sci. USA 88, 10540–10543.
  4. [17]Greenberg, S. G. & Davies, P. (1990) Proc. Natl. Acad. Sci. USA 87, 5827-5831.
  5. [21]Wischik, C., Novak, M., Thogersen, H., Edwards, P., Runswick, M., Jakes, R., Walker, J., Milstein, C., Roth, M. & Klug, A. (1988) Proc. Natl. Acad. Sci. USA 85, 4506–4510.
  6. [32]Shigenaga, M. K., Hagen, T. M. & Ames, B. N. (1994) Proc. Natl. Acad. Sci. USA 91, 10771–10778.
  7. [35]Strittmatter, W. J., Weisgraber, K. H., Goedert, M., Saunders, A. M., Huang, D., Corder, E. H., Dong, L. M., Jakes, R., Alberts, M. J., Gilbert, J. R., Han, S. H., Hulette, C., Einstein, G., Schmechel, D., Pericak-Vance, M. & Roses, A. (1994) Exp. Neurol. 125, 163–171.

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Metadata

Authors
Schweers, O., Mandelkow, E. M., Biernat, J., & Mandelkow, E.
Affiliations
Max-Planck Unit for Structural Molecular Biology, c/o Deutsches Elektronen Synchroton, Hamburg, Germany.
Venue
Proceedings of the National Academy of Sciences
Published
1995-08-29
Volume
92
Issue
18
Pages
8463-8467
ISSN
  • 0027-8424
  • 1091-6490
Cited by
334
References
4
Language
en

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