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A Multistage Pathway for Human Prion Protein Aggregation in Vitro: From Multimeric Seeds to β-Oligomers and Nonfibrillar Structures
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, Janet Moradian-Oldak, Man-Sun Sy§, and James J. De Yoreo*†
Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California 90033, United States Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States# Author Present Address
Singapore Eye Research Institute, 7 Hospital Drive, Block C, 02-02, Singapore 169611.
Section:Abstract
Aberrant protein aggregation causes numerous neurological diseases including Creutzfeldt–Jakob disease (CJD), but the aggregation mechanisms remain poorly understood. Here, we report AFM results on the formation pathways of β-oligomers and nonfibrillar aggregates from wild-type full-length recombinant human prion protein (WT) and an insertion mutant (10OR) with five additional octapeptide repeats linked to familial CJD. Upon partial denaturing, seeds consisting of 3–4 monomers quickly appeared. Oligomers of 
11–22 monomers then formed through direct interaction of seeds, rather than by subsequent monomer attachment. All larger aggregates formed through association of these β-oligomers. Although both WT and 10OR exhibited identical aggregation mechanisms, the latter oligomerized faster due to lower solubility and, hence, thermodynamic stability. This novel aggregation pathway has implications for prion diseases as well as others caused by protein aggregation.
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This article has been cited by 1 ACS Journal articles (1 most recent appear below).
In situ AFM Study of Amelogenin Assembly and Disassembly Dynamics on Charged Surfaces Provides Insights on Matrix Protein Self-Assembly
Chun-Long Chen, Keith M. Bromley, Janet Moradian-Oldak, and James J. DeYoreoJournal of the American Chemical Society2011 133 (43), 17406-17413In situ AFM Study of Amelogenin Assembly and Disassembly Dynamics on Charged Surfaces Provides Insights on Matrix Protein Self-Assembly
Chun-Long Chen, Keith M. Bromley, Janet Moradian-Oldak, and James J. DeYoreoJournal of the American Chemical Society2011 133 (43), 17406-17413Because self-assembly of matrix proteins is a key step in hard tissue mineralization, developing an understanding of the assembly pathways and underlying mechanisms is likely to be important for successful hard tissue engineering. While many studies of ...
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History
- Published In Issue June 08, 2011
- Article ASAPMay 17, 2011
- Just Accepted ManuscriptMay 02, 2011
- Received: December 30, 2010
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