Molecular Dynamics Simulations of the Tau Amyloid Fibril Core Dimer at the Surface of a Lipid Bilayer Model: I. In Alzheimer’s Disease

The Journal of Physical Chemistry B, Год журнала: 2022, Номер 126(26), С. 4849 - 4856

Опубликована: Июнь 27, 2022

A tau R3–R4 domain spanning residues 306–378 was shown to form an amyloid fibril core of a full-length in the brain patients with Alzheimer's disease. Recently, we studied dynamics monomer at surface lipid bilayer model and revealed deep insertion amino acids PHF6 motif (residues 306–311) its flanking residues. Here, explore membrane-associated conformational ensemble dimer by means atomistic molecular dynamics. Similar simulation, has propensity β-hairpin-like conformation. Unlike monomer, shows C-terminal R4 region transient adsorption motif. Taken together, these results reveal multiplicity modes into membranes depending on oligomer size.

Язык: Английский

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Modulation of Primary and Secondary Processes in Tau Fibril Formation by Salt-Induced Dynamics

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(6), С. 1242 - 1253

Опубликована: Март 4, 2024

The initial stages of amyloid fibrilization begin with the monomers populating aggregation-prone conformers. Characterization such conformers is crucial in study neurodegenerative diseases. current characterizes aggregation pathway two tau protein constructs that have been recently demonstrated to form Alzheimer's (AD) fibril structures divalent ions and chronic traumatic encephalopathy (CTE) monovalent ions. results highlight involvement identical residues both primary secondary processes AD CTE propagation. Nuclear magnetic resonance relaxation experiments reveal increased flexibility motifs 321KCGS within R3 364PGGGN R4 presence MgCl2/NaCl, correlating faster kinetics indicating efficient nucleation. Notably, seeded absence metal are strikingly different. This correlates overall sign 15N-ΔR2 profile specifying dominant mechanism involved process aggregation.

Язык: Английский

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Generating Ensembles of Dynamic Misfolding Proteins

Frontiers in Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Март 31, 2022

The early stages of protein misfolding and aggregation involve disordered partially folded conformers that contain a high degree dynamic disorder. These species may undergo large-scale intra-molecular motions intrinsically (IDP) precursors, or flexible, low affinity inter-molecular binding in oligomeric assemblies. In both cases, generating atomic level visualization the interconverting captures conformations explored their physico-chemical properties remains hugely challenging. How specific sub-ensembles are on-pathway to into amyloid can be identified from aggregation-resilient counterparts within these large heterogenous pools rapidly moving molecules represents an additional complexity. Here, we describe current experimental computational approaches designed capture nature aggregation, discuss potential challenges describing because ensemble averaging restraints arise on millisecond timescale. We give perspective how machine learning methods used extract aggregation-relevant provide two examples such approach which interactions defined ensembles α-synuclein (αSyn) β

Язык: Английский

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Nuclear magnetic resonance/single molecule fluorescence combinations to study dynamic protein systems

Current Opinion in Structural Biology, Год журнала: 2023, Номер 82, С. 102659 - 102659

Опубликована: Июль 25, 2023

Many proteins require different structural states or conformations for function, and intrinsically disordered proteins, i.e. without stable three-dimensional structure, are certainly an extreme. Single molecule fluorescence nuclear magnetic resonance (NMR) spectroscopy both exceptionally well suited to decipher describe these their interconversion. Different time scales, from picoseconds several milliseconds, can be addressed by techniques. The length scales probed the sample requirements (e.g. concentration, molecular weight, complexity) are, however, vastly different, making NMR single excellent combination integrated studies. Here, we review recently undertaken approaches combined use of study protein dynamics.

Язык: Английский

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Tau P301L mutation promotes core 4R tauopathy fibril fold through near-surface water structuring and conformational rearrangement

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 28, 2023

Tau forms toxic fibrillar aggregates in a family of neurodegenerative diseases known as tauopathies. The faithful replication tauopathy-specific fibril structures is critical gap for developing diagnostic and therapeutic tools. This study debuts strategy identifying segment tau that folding motif characteristic tauopathies isolating it standalone peptide form seeding-competent fibrils. 19-residue jR2R3 (295-313) spanning the R2/R3 splice junction tau, presence P301L, amyloid fragment contains hydrophobic VQIVYK hexapeptide part core every pathological structure solved to-date an intramolecular counter-strand stabilizes strand-loop-strand (SLS) observed 4R tauopathy shows P301L exhibits duality effects: lowers barrier to adopt aggregation-prone conformations enhances local structuring water around mutation site facilitates site-specific dewetting in-register stacking cross β-sheets. We solve 3 Å cryo-EM jR2R3-P301L fibrils with pseudo 2 1 screw symmetry which each half fibril's cross-section two peptides. One chain adopts SLS fold found stabilized by second wrapping fold, reminiscent 3-fold 4-fold These are able template full length prion-like fashion. presents first step towards designing specific aggregation pathway engineering minimal prion building block, jR2R3, can propagate distinct disease folds. present discovery P301L-among widest used mutations cell animal models Alzheimer's Disease-destabilizes aggregation-prohibiting internal hairpin surface serves entropic hotspot exert hyper-localized effect jR2R3. Our suggests may be more suitable include modeling than modelling Disease, powerful tools purpose

Язык: Английский

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