Abstract | BACKGROUND: METHODOLOGY/PRINCIPAL FINDINGS: As evidenced by thioflavin T binding and turbidity assays, transmission electron microscopy, and circular dichroism, fibril-forming motifs are essential and sufficient for the fibrillization of microtubule-associated protein Tau: only when both of its fibril-forming motifs, PHF6 and PHF6*, are deleted can recombinant human Tau fragment Tau(244-372) lose its ability to form fibrils, and the insertion of unrelated fibril-forming motifs from other amyloidogenic proteins, such as human prion protein, yeast prion protein, human α- synuclein, and human amyloid β, into the disabled Tau protein can retrieve its ability to form fibrils. Furthermore, this retrieval is independent of the insertion location on Tau(244-372). CONCLUSIONS/SIGNIFICANCE: We demonstrate for the first time that insertion of fibril-forming motifs can replace PHF6/PHF6* motifs, driving human Tau protein to form fibrils with different morphologies and different kinetic parameters. Our results suggest that fibril-forming motifs play a key role in the fibrillization of human Tau protein and could be the determinants of amyloidogenic proteins tending to misfold, thereby causing the initiation and development of neurodegenerative diseases. Our study also touches on the importance of amyloid "strains": changes to the amyloidgenic driver region results in altered structural morphologies at the macromolecular level.
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Authors | Sheng-Rong Meng, Ying-Zhu Zhu, Tong Guo, Xiao-Ling Liu, Jie Chen, Yi Liang |
Journal | PloS one
(PLoS One)
Vol. 7
Issue 6
Pg. e38903
( 2012)
ISSN: 1932-6203 [Electronic] United States |
PMID | 22701727
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amyloid
- Benzothiazoles
- DNA Primers
- Recombinant Proteins
- Thiazoles
- tau Proteins
- thioflavin T
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Topics |
- Amino Acid Motifs
(genetics)
- Amyloid
(biosynthesis)
- Benzothiazoles
- Circular Dichroism
- DNA Primers
(genetics)
- Humans
- Microscopy, Electron, Transmission
- Plasmids
(genetics)
- Protein Folding
- Recombinant Proteins
(metabolism)
- Thiazoles
(metabolism)
- tau Proteins
(genetics)
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