A Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric Aggregates

被引:94
作者
Auer, Stefan [1 ]
Meersman, Filip [2 ]
Dobson, Christopher M. [3 ]
Vendruscolo, Michele [3 ]
机构
[1] Univ Leeds, Ctr Self Organising Mol Syst, Leeds, W Yorkshire, England
[2] Katholieke Univ Leuven, Dept Chem, Louvain, Belgium
[3] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England
基金
英国惠康基金;
关键词
D O I
10.1371/journal.pcbi.1000222
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
The presence of oligomeric aggregates, which is often observed during the process of amyloid formation, has recently attracted much attention because it has been associated with a range of neurodegenerative conditions including Alzheimer's and Parkinson's diseases. We provide a description of a sequence-indepedent mechanism by which polypeptide chains aggregate by forming metastable oligomeric intermediate states prior to converting into fibrillar structures. Our results illustrate that the formation of ordered arrays of hydrogen bonds drives the formation of beta-sheets within the disordered oligomeric aggregates that form early under the effect of hydrophobic forces. Individual beta-sheets initially form with random orientations and subsequently tend to align into protofilaments as their lengths increase. Our results suggest that amyloid aggregation represents an example of the Ostwald step rule of first-order phase transitions by showing that ordered cross-beta structures emerge preferentially from disordered compact dynamical intermediate assemblies.
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页数:7
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共 39 条
[1]   Quantitative prediction of crystal-nucleation rates for spherical colloids: A computational approach [J].
Auer, S ;
Frenkel, D .
ANNUAL REVIEW OF PHYSICAL CHEMISTRY, 2004, 55 :333-361
[2]   Importance of metastable states in the free energy landscapes of polypeptide chains [J].
Auer, Stefan ;
Miller, Mark A. ;
Krivov, Sergei V. ;
Dobson, Christopher M. ;
Karplus, Martin ;
Vendruscolo, Michele .
PHYSICAL REVIEW LETTERS, 2007, 99 (17)
[3]   Characterization of the nucleation barriers for protein aggregation and amyloid formation [J].
Auer, Stefan ;
Dobson, Christopher M. ;
Vendruscolo, Michele .
HFSP JOURNAL, 2007, 1 (02) :137-146
[4]   Physics of proteins [J].
Banavar, Jayanth R. ;
Maritan, Amos .
ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE, 2007, 36 :261-280
[5]   Molecular dynamics simulations of Alzheimer's β-amyloid protofilaments [J].
Buchete, NV ;
Tycko, R ;
Hummer, G .
JOURNAL OF MOLECULAR BIOLOGY, 2005, 353 (04) :804-821
[6]   Structural reorganisation and potential toxicity of oligomeric species formed during the assembly of amyloid fibrils [J].
Cheon, Mookyung ;
Chang, Iksoo ;
Mohanty, Sandipan ;
Luheshi, Leila M. ;
Dobson, Christopher M. ;
Vendruscolo, Michele ;
Favrin, Giorgio .
PLOS COMPUTATIONAL BIOLOGY, 2007, 3 (09) :1727-1738
[7]  
Cheon M, 2008, FRONT BIOSCI-LANDMRK, V13, P5614
[8]   Protein misfolding, functional amyloid, and human disease [J].
Chiti, Fabrizio ;
Dobson, Christopher M. .
ANNUAL REVIEW OF BIOCHEMISTRY, 2006, 75 :333-366
[9]  
DERREUMAUX P, 2007, J CHEM PHYS, V125
[10]   High hydrostatic pressure dissociates early aggregates of TTR105-115, but not the mature amyloid fibrils [J].
Dirix, C ;
Meersman, F ;
MacPhee, CE ;
Dobson, CM ;
Heremans, K .
JOURNAL OF MOLECULAR BIOLOGY, 2005, 347 (05) :903-909