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Dynamics of Serine-8 Side-Chain in Amyloid-β Fibrils and Fluorenylmethyloxycarbonyl Serine Amino Acid, Investigated by Solid-State Deuteron NMR.

ABSTRACT: Serine side-chains are strategic sites of post-translational modifications, and it is important to establish benchmarks of their internal dynamics. In this work, we compare the dynamics of serine side-chains in several biologically important systems: serine-8 in the disordered domain of Aβ_1-40 fibrils in the hydrated and dry states and fluorenylmethyloxycarbonyl (Fmoc) serine with the bulky group that mimics the hydrophobicity of the fibril contacts yet lacks the complexity of the protein system. Using deuterium solid-state NMR static line shape and longitudinal relaxation techniques in the 310 to 180 K temperature range, we compare the main features of the dynamics in these systems. The main motional modes in the fibrils are large-scale fluctuations in the hydrated state of the fibrils as well as local motions such as 3-site jumps of the C^β deuterons at high temperatures and small-angle fluctuations of the C^α-C^β axis at low temperatures. In the hydrated fibrils, two distinct states are present with vastly different extents of large-scale diffusive motions and 3-site-jump rate constants. The hydrated state at the physiological conditions is dominated by the "free" state undergoing large-scale diffusive motions and very fast local 3-site jumps, while in the "bound" state, these large-scale motions are quenched due to transient inter- and intramolecular interactions. Additionally, in the bound state, the 3-site-jump motions are orders of magnitude slower. Details of the dynamics in the serine side-chain are dependent on fine structural features and hydration levels of the systems.

SUBMITTER: Vugmeyster L

PROVIDER: S-EPMC7875318 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The microtubule-associated protein tau aggregates into distinct neurofibrillary tangles in brains afflicted with multiple neurodegenerative diseases such as Alzheimer's disease and corticobasal degeneration (CBD). The mechanism of tau misfolding and aggregation is poorly understood. Determining the structure, dynamics, and water accessibility of tau filaments may provide insight into the pathway of tau misfolding. Here, we investigate the hydration and dynamics of the β-sheet core of heparin-fibrillized 0N4R tau using solid-state nuclear magnetic resonance spectroscopy. This β-sheet core consists of the second and third microtubule-binding repeats, R2 and R3, respectively, which form a hairpin. Water-edited two-dimensional (2D) 13C-13C and 15N-13C correlation spectra show that most residues in R2 and R3 domains have low water accessibility, indicating that this hairpin is surrounded by other proteinaceous segments. However, a small number of residues, especially S285 and S316, are well hydrated compared to other Ser and Thr residues, suggesting that there is a small water channel in the middle of the hairpin. To probe whether water accessibility correlates with protein dynamics, we measured the backbone N-H dipolar couplings of the β-sheet core. Interestingly, residues in the fourth microtubule-binding repeat, R4, show rigid-limit N-H dipolar couplings, even though this domain exhibits weaker intensities in the 2D 15N-13C correlation spectra. These results suggest that the R4 domain participates in cross-β hydrogen bonding in some of the subunits but exhibits dynamic disorder in other subunits. Taken together, these hydration and dynamics data indicate that the R2-R3 hairpin of 0N4R tau is shielded from water by other proteinaceous segments on the exterior but contains a small water pore in the interior. This structural topology has various similarities with the CBD tau fibril structure but also shows specific differences. The disorder of the R4 domain and the presence of a small water channel in the heparin-fibrillized 4R tau have implications for the structure of tau fibrils in diseased brains.

Dataset Information

Dynamics of Serine-8 Side-Chain in Amyloid-β Fibrils and Fluorenylmethyloxycarbonyl Serine Amino Acid, Investigated by Solid-State Deuteron NMR.

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