| A molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization. | |
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MedLine Citation:
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PMID: 14664580 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Aberrant protein oligomerization is an important pathogenetic process in vivo. In Alzheimer's disease (AD), the amyloid beta-protein (Abeta) forms neurotoxic oligomers. The predominant in vivo Abeta alloforms, Abeta40 and Abeta42, have distinct oligomerization pathways. Abeta42 monomers oligomerize into pentamer/hexamer units (paranuclei) which self-associate to form larger oligomers. Abeta40 does not form these paranuclei, a fact which may explain the particularly strong linkage of Abeta42 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 Met(35) is associated with altered Abeta assembly, we examined the role of Met(35) in controlling Abeta oligomerization. Oxidation of Met(35) in Abeta42 blocked paranucleus formation and produced oligomers indistinguishable in size and morphology from those produced by Abeta40. Systematic structural alterations of the C(gamma)(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 Abeta42 paranuclei through selective oxidation of Met(35) thus represents a potential therapeutic approach for AD. |
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Authors:
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Gal Bitan; Bogdan Tarus; Sabrina S Vollers; Hilal A Lashuel; Margaret M Condron; John E Straub; David B Teplow |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of the American Chemical Society Volume: 125 ISSN: 0002-7863 ISO Abbreviation: J. Am. Chem. Soc. Publication Date: 2003 Dec |
Date Detail:
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Created Date: 2003-12-10 Completed Date: 2004-02-26 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 7503056 Medline TA: J Am Chem Soc Country: United States |
Other Details:
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Languages: eng Pagination: 15359-65 Citation Subset: IM |
Affiliation:
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Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amyloid
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biosynthesis*,
chemistry Amyloid beta-Protein / chemistry, metabolism* Methionine / chemistry, metabolism* Oxidation-Reduction |
| Grant Support | |
ID/Acronym/Agency:
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AG 18921/AG/NIA NIH HHS; NS 38328/NS/NINDS NIH HHS; NS 44147/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amyloid; 0/Amyloid beta-Protein; 63-68-3/Methionine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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