title: How Does Hyperphopsphorylation Promote Tau Aggregation and Modulate Filament Structure and Stability?
abstract: Tau proteins are hyperphosphorylated at common sites in their N- and C-terminal domains in at least three neurodegenerative diseases, Parkinson, dementia with Lewy bodies, and Alzheimer's, suggesting specific pathology but general mechanism. Full-length human tau filament comprises a rigid core and a two-layered fuzzy coat. Tau is categorized into two groups of isoforms, with either four repeats (R1-R4) or three repeats (R1, R3, and R4); their truncated constructs are respectively called K18 and K19. Using multiscale molecular dynamics simulations, we explored the conformational consequences of hyperhposphorylation on tau's repeats. Our lower conformational energy filament models suggest a rigid filament core with a radius of ∼30 to 40 Å and an outer layer with a thickness of ∼140 Å consisting of a double-layered polyelectrolyte. The presence of the phosphorylated terminal domains alters the relative stabilities in the K18 ensemble, thus shifting the populations of the full-length filaments. However, the structure with the straight repeats in the core region is still the most stable, similar to the truncated K18 peptide species without the N- and C-terminus. Our simulations across different scales of resolution consistently reveal that hyperphosphorylation of the two terminal domains decreases the attractive interactions among the N- and C-terminus and repeat domain. To date, the relationship on the conformational level between phosphorylation and aggregation has not been understood. Our results suggest that the exposure of the repeat domain upon hyperphosphorylation could enhance tau filament aggregation. Thus, we discovered that even though these neurodegenerative diseases vary and their associated tau filaments are phosphorylated to different extents, remarkably, the three pathologies appear to share a common tau aggregation mechanism.
authors: School of Chemistry, Dalian University of Technology , Dalian 116024, China.
authors: Liang
authors: L
authors: Xu
authors: Department of Chemical & Biomolecular Engineering, The University of Akron , Akron, Ohio 44325, United States.
authors: Jie
authors: J
authors: Zheng
authors: Department of Chemistry and Biochemistry, University of Denver , Denver, Colorado 80208, United States.
authors: Martin
authors: M
authors: Margittai
authors: Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.|Basic Research Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, NCI , Frederick, Maryland 21702, United States.
authors: Ruth
authors: R
authors: Nussinov
authors: Basic Research Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, NCI , Frederick, Maryland 21702, United States.
authors: Buyong
authors: B
authors: Ma
mesh_terms: D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D066329:Protein Aggregates / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D016875:tau Proteins
keywords: Alzheimer’s disease; Tau; amyloid; hyperphosphorylation; paired helical filaments