Document Detail


Elongated oligomers in beta2-microglobulin amyloid assembly revealed by ion mobility spectrometry-mass spectrometry.
MedLine Citation:
PMID:  20351246     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The key to understanding amyloid disease is the characterization of oligomeric species formed during the early stages of fibril assembly. Here we have used electrospray ionisation-ion mobility spectrometry-mass spectrometry to identify and structurally characterize the oligomers formed during amyloid assembly from beta(2)-microglobulin (beta(2)m). Beta(2)m oligomers are shown to have collision cross-sections consistent with monomeric units arranged in elongated assemblies prior to fibril formation. Direct observation, separation, and quantification of transient oligomeric species reveals that monomers to tetramers are populated through the lag phase with no evidence for the significant population of larger oligomeric species under the conditions employed. The dynamics of each oligomeric species were monitored directly within the ensemble at concentrations commensurate with amyloid formation by observing the subunit exchange of (14)N- and (15)N-labeled oligomers. Analysis of the data revealed a decrease in oligomer dynamics concomitant with increasing oligomer size and the copopulation of dynamic dimeric and trimeric species with more stable trimeric and tetrameric species. The results presented map the events occurring during the lag phase of fibril formation and give a clear insight into the structural characteristics and dynamic nature of the beta(2)m oligomers, demonstrating the existence of elongated assemblies arising from an intact amyloidogenic protein during fibril formation.
Authors:
David P Smith; Sheena E Radford; Alison E Ashcroft
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-29
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-14     Completed Date:  2010-05-14     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6794-8     Citation Subset:  IM    
Affiliation:
Astbury Centre for Structural Molecular Biology, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Amyloid / chemistry*
Amyloidosis / metabolism
Dimerization
Escherichia coli / metabolism
Humans
Hydrogen-Ion Concentration
Ions / chemistry
Nitrogen Isotopes / chemistry
Protein Folding
Spectrometry, Mass, Electrospray Ionization / methods*
Urea / chemistry
beta 2-Microglobulin / chemistry*
Grant Support
ID/Acronym/Agency:
BB/D010284/1//Biotechnology and Biological Sciences Research Council; BB/E012558/1//Biotechnology and Biological Sciences Research Council
Chemical
Reg. No./Substance:
0/Amyloid; 0/Ions; 0/Nitrogen Isotopes; 0/beta 2-Microglobulin; 57-13-6/Urea
Comments/Corrections

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