Document Detail


A molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization.
MedLine Citation:
PMID:  14664580     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Gal Bitan; Bogdan Tarus; Sabrina S Vollers; Hilal A Lashuel; Margaret M Condron; John E Straub; David B Teplow
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  125     ISSN:  0002-7863     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2003 Dec 
Date Detail:
Created Date:  2003-12-10     Completed Date:  2004-02-26     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15359-65     Citation Subset:  IM    
Affiliation:
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
Amyloid / biosynthesis*,  chemistry
Amyloid beta-Protein / chemistry,  metabolism*
Methionine / chemistry,  metabolism*
Oxidation-Reduction
Grant Support
ID/Acronym/Agency:
AG 18921/AG/NIA NIH HHS; NS 38328/NS/NINDS NIH HHS; NS 44147/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
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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