Abstract
BackgroundThe misfolding of amyloidogenic proteins including human Tau protein, human prion protein, and human α-synuclein is involved in neurodegenerative diseases such as Alzheimer disease, prion disease, and Parkinson disease. Although a lot of research on such amyloidogenic proteins has been done, we do not know the determinants that drive these proteins to form fibrils and thereby induce neurodegenerative diseases. In this study, we want to know the role of fibril-forming motifs from such amyloidogenic proteins in the fibrillization of human Tau protein.Methodology/Principal FindingsAs 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 Tau244–372 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 Tau244–372.Conclusions/SignificanceWe 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.
Highlights
The abnormal aggregation of proteins plays an important role in the functions of proteins: the misfolding of amyloidogenic proteins can cause serious neurodegenerative diseases, such as human Tau protein and human amyloid b peptide in Alzheimer disease, human a-synuclein in Parkinson disease, human polyglutamine-containing peptides in Huntington disease, and human/ bovine prion proteins in prion diseases [1,2,3,4,5,6,7]; some are helpful for organisms to survive in environmental threats, for example, Sup35 in yeast; and some are required for the normal functions of the organisms [7], such as curlin in E. coli [7,8], Pmel17 in the pigmentation of mammals [9], and many peptide or protein hormones are stored in the form of amyloid fibrils [10]
We investigated the potential primary structure determinants of filament formation of human Tau protein by using several biophysical methods, such as assays based on thioflavin T (ThT) binding and turbidity, transmission electron microscopy (TEM), and far-UV circular dichroism (CD)
It has been reported that PHF6 and PHF6* are both very important for the fibrillization of human Tau protein but only PHF6 is essential for filament formation [23]
Summary
The abnormal aggregation of proteins plays an important role in the functions of proteins: the misfolding of amyloidogenic proteins can cause serious neurodegenerative diseases, such as human Tau protein and human amyloid b peptide in Alzheimer disease, human a-synuclein in Parkinson disease, human polyglutamine-containing peptides in Huntington disease, and human/ bovine prion proteins in prion diseases [1,2,3,4,5,6,7]; some are helpful for organisms to survive in environmental threats, for example, Sup in yeast; and some are required for the normal functions of the organisms [7], such as curlin in E. coli [7,8], Pmel in the pigmentation of mammals [9], and many peptide or protein hormones are stored in the form of amyloid fibrils [10].the potential of misfolding of proteins are influenced by many factors: abnormal cellular environments, including aberrant ion concentrations [11,12] and unbalanced oxidative stress [13]; covalent modification of proteins, such as the hyperphosphorylation of Tau protein [13,14] and aged glycation of b2-microglobulin [15,16]; crowded physiological environments [14,17]; and pathogenic mutations in amyloidogenic proteins which enable or promote their ability of aggregation [13,18]. A lot of research on such amyloidogenic proteins has been done, we do not know the determinants that drive these proteins to form fibrils and thereby induce neurodegenerative diseases Using methods such as NMR [24], proline-scanning [25], and positive fibrillization assays [26,27], scientists have identified some fibril-forming motifs from the reported amyloid proteins. We want to know the role of fibril-forming motifs from such amyloidogenic proteins in the fibrillization of human Tau protein
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