A Molecular Switch in Amyloid Assembly: Met35 and Amyloid β-Protein Oligomerization

Gal Bitan, Bogdan Tarus, Sabrina S. Vollers, Hilal A. Lashuel, Margaret M. Condron, John E. Straub, David B. Teplow

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Aberrant protein oligomerization is an important pathogenetic process in vivo. In Alzheimer's disease (AD), the amyloid β-protein (Aβ) forms neurotoxic oligomers. The predominant in vivo Aβ alloforms, Aβ40 and Aβ42, have distinct oligomerization pathways. Aβ42 monomers oligomerize into pentamer/hexamer units (paranuclei) which self-associate to form larger oligomers. Aβ40 does not form these paranuclei, a fact which may explain the particularly strong linkage of Aβ42 with AD. Here, we sought to determine the structural elements controlling paranucleus formation as a first step toward the development of strategies for treating AD. Because oxidation of Met35 is associated with altered Aβ assembly, we examined the role of Met35 in controlling Aβ oligomerization. Oxidation of Met35 in Aβ42 blocked paranucleus formation and produced oligomers indistinguishable in size and morphology from those produced by Aβ40. Systematic structural alterations of the Cγ 35-substituent group revealed that its electronic nature, rather than its size (van der Waals volume), was the factor controlling oligomerization pathway choice. Preventing assembly of toxic Aβ42 paranuclei through selective oxidation of Met35 thus represents a potential therapeutic approach for AD.

Original languageEnglish
Pages (from-to)15359-15365
Number of pages7
JournalJournal of the American Chemical Society
Volume125
Issue number50
DOIs
Publication statusPublished - 17 Dec 2003
Externally publishedYes

Fingerprint

Amyloidogenic Proteins
Oligomerization
Amyloid
Alzheimer Disease
Switches
Oligomers
Oxidation
Serum Amyloid A Protein
Poisons
Monomers
Proteins

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Bitan, G., Tarus, B., Vollers, S. S., Lashuel, H. A., Condron, M. M., Straub, J. E., & Teplow, D. B. (2003). A Molecular Switch in Amyloid Assembly: Met35 and Amyloid β-Protein Oligomerization. Journal of the American Chemical Society, 125(50), 15359-15365. https://doi.org/10.1021/ja0349296

A Molecular Switch in Amyloid Assembly : Met35 and Amyloid β-Protein Oligomerization. / Bitan, Gal; Tarus, Bogdan; Vollers, Sabrina S.; Lashuel, Hilal A.; Condron, Margaret M.; Straub, John E.; Teplow, David B.

In: Journal of the American Chemical Society, Vol. 125, No. 50, 17.12.2003, p. 15359-15365.

Research output: Contribution to journalArticle

Bitan, G, Tarus, B, Vollers, SS, Lashuel, HA, Condron, MM, Straub, JE & Teplow, DB 2003, 'A Molecular Switch in Amyloid Assembly: Met35 and Amyloid β-Protein Oligomerization', Journal of the American Chemical Society, vol. 125, no. 50, pp. 15359-15365. https://doi.org/10.1021/ja0349296
Bitan G, Tarus B, Vollers SS, Lashuel HA, Condron MM, Straub JE et al. A Molecular Switch in Amyloid Assembly: Met35 and Amyloid β-Protein Oligomerization. Journal of the American Chemical Society. 2003 Dec 17;125(50):15359-15365. https://doi.org/10.1021/ja0349296
Bitan, Gal ; Tarus, Bogdan ; Vollers, Sabrina S. ; Lashuel, Hilal A. ; Condron, Margaret M. ; Straub, John E. ; Teplow, David B. / A Molecular Switch in Amyloid Assembly : Met35 and Amyloid β-Protein Oligomerization. In: Journal of the American Chemical Society. 2003 ; Vol. 125, No. 50. pp. 15359-15365.
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