The effect of an amyloidogenic intrinsically disordered protein, α-synuclein, which is associated with Parkinson's disease (PD), on the conformational dynamics of a DNA hairpin (DNA-HP) was studied by employing the single-molecule Förster resonance energy transfer method. The open-to-closed conformational equilibrium of the DNA-HP is drastically affected by binding of monomeric α-synuclein to the loop region of the DNA-HP. Formation of a protein-bound intermediate conformation is fostered in the presence of an aqueous two-phase system mimicking intracellular liquid-liquid phase separation. Using pressure modulation, additional mechanistic information about the binding complex could be retrieved. Hence, in addition to toxic amyloid formation, α-synuclein may alter expression profiles of disease-modifying genes in PD. Furthermore, these findings might also have significant bearings on the understanding of the physiology of organisms thriving at high pressures in the deep sea.
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http://dx.doi.org/10.1002/chem.202002119 | DOI Listing |
Proc Natl Acad Sci U S A
January 2025
Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX 75080.
The TRAMP complex contains two enzymatic activities essential for RNA processing upstream of the nuclear exosome. Within TRAMP, RNA is 3' polyadenylated by a subcomplex of Trf4/5 and Air1/2 and unwound 3' to 5' by Mtr4, a DExH helicase. The molecular mechanisms of TRAMP assembly and RNA shuffling between the two TRAMP catalytic sites are poorly understood.
View Article and Find Full Text PDFSci Adv
January 2025
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Hyperpolarization-activated and cyclic nucleotide-gated (HCN) ion channels are members of the cyclic nucleotide-binding family and are crucial for regulating cellular automaticity in many excitable cells. HCN channel activation contributes to pain perception, and propofol, a widely used anesthetic, acts as an analgesic by inhibiting the voltage-dependent activity of HCN channels. However, the molecular determinants of propofol action on HCN channels remain unknown.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
Background: Reversible post-translational modifications, phosphorylation and dephosphorylation, on tau protein play a critical role in the microtubule (MT) modulation. However, abnormal tau phosphorylation, which occurs in tauopathies such as Alzheimer's disease (AD), causes the dissociation of tau from MTs. The dissociated tau then aggregates into sequent forms from soluble oligomers to paired helical filaments (PHF), and insoluble neurofibrillary tangles (NFTs), a hallmark of AD.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Case Western Reserve University, Cleveland, OH, USA.
Background: Pathological tau forms from Alzheimer's disease (AD) brains act as seeds, replicating in cells and forming tau aggregates in a template-like manner. The exploration of this prion-like pathogenic mechanism has predominantly occurred in transgenic mice and cell systems that overexpress tau protein and its truncated forms with pro-aggregation mutations. However, these systems do not entirely capture the propagation kinetics and template conformational changes of various tau seeds.
View Article and Find Full Text PDFFront Immunol
January 2025
Institute for Infection Research and Vaccine Development (IIRVD), Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Introduction: Vaccine platforms such as viral vectors and mRNA can accelerate vaccine development in response to newly emerging pathogens, as demonstrated during the COVID-19 pandemic. However, the differential effects of platform and antigen insert on vaccine immunogenicity remain incompletely understood. Innate immune responses induced by viral vector vaccines are suggested to have an adjuvant effect for subsequent adaptive immunity.
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