Cryo-EM reconstruction of helical polymers: Beyond the simple cases DOI
Mark A. B. Kreutzberger, Ravi R. Sonani, Edward H. Egelman

et al.

Quarterly Reviews of Biophysics, Journal Year: 2024, Volume and Issue: 57

Published: Jan. 1, 2024

Helices are one of the most frequently encountered symmetries in biological assemblies. Helical symmetry has been exploited electron microscopic studies as a limited number filament images, principle, can provide all information needed to do three-dimensional reconstruction polymer. Over past 25 years, reconstructions helical polymers from cryo-EM images have shifted completely Fourier-Bessel methods single-particle approaches. The approaches allowed people surmount problem that very few crystalline order, and despite flexibility heterogeneity present these polymers, reaching resolution where accurate atomic models be built now become standard. While determining correct may simple for something like F-actin, many other particularly those formed small peptides, it much more challenging. This review discusses why determination problematic, trial-and-error still best approach. Studies macromolecular assemblies, such icosahedral capsids, usually found not imposing leads great reduction while at same time revealing possibly interesting asymmetric features. We show certain assemblies sometimes lead greatly improved resolution. Further, case supercoiled flagellar filaments bacteria archaea, we imposition only wrong, but is necessary, obscures mechanisms whereby supercoil.

Language: Английский

A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion DOI Creative Commons
Jaime Santos, Jorge Cuéllar, Irantzu Pallarès

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(18), P. 12702 - 12711

Published: April 29, 2024

Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development oligomer-targeting therapeutics is constrained by our limited knowledge their structure and molecular determinants driving conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) a nanomolar peptide binder oligomers that inhibits blocking oligomer-to-fibril conversion. Here, we investigate binding PSMα3 discover mechanistic basis this protective activity. We find selectively targets an N-terminal motif (residues 36–61) populates distinct conformation mono- oligomeric states. This region plays pivotal role as its absence renders central NAC domain insufficient prompt structural transition. The hereditary mutation G51D, associated with early onset disease, causes conformational fluctuation region, leading delayed accumulation resistant remodeling chaperones. Overall, findings unveil new targetable oligomers, advance comprehension oligomer-to-amyloid fibril conversion, reveal facet pathogenic mutations.

Language: Английский

Citations

12
The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges DOI Open Access

Huiting Zheng,

Huimin Sun, Qixu Cai

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4969 - 4969

Published: May 2, 2024

Tau protein misfolding and aggregation are pathological hallmarks of Alzheimer's disease over twenty neurodegenerative disorders. However, the molecular mechanisms tau in vivo remain incompletely understood. There two types aggregates brain: soluble (oligomers protofibrils) insoluble filaments (fibrils). Compared to filamentous aggregates, more toxic exhibit prion-like transmission, providing seeds for templated misfolding. Curiously, its native state, is a highly soluble, heat-stable that does not form fibrils by itself, even when hyperphosphorylated. In vitro studies have found negatively charged molecules such as heparin, RNA, or arachidonic acid generally required induce aggregation. Two recent breakthroughs provided new insights into mechanisms. First, an intrinsically disordered protein, undergo liquid-liquid phase separation (LLPS) both inside cells. Second, cryo-electron microscopy has revealed diverse fibrillar conformations associated with different Nonetheless, only core structurally resolved, remainder appears "fuzzy coat". From this review, it further (1) clarify role LLPS aggregation; (2) unveil structural features aggregates; (3) understand involvement fuzzy coat regions oligomer fibril formation.

Language: Английский

Citations

12
Impacts of D-aspartate on the aggregation kinetics and structural polymorphism of amyloid β peptide 1-42 DOI

Li Li Hsiao,

Chih‐Hsuan Lee, Karine Mazmanian

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169092 - 169092

Published: March 1, 2025

Language: Английский

Citations

1
Automated microscopic measurement of fibrinaloid microclots and their degradation by nattokinase, the main natto protease DOI Creative Commons
Justine M. Grixti, Chrispian W. Theron, J. Enrique Salcedo-Sora

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 7, 2024

Abstract Nattokinase, from the Japanese fermented food natto, is a protease with fibrinolytic activity that can thus degrade conventional blood clots. In some cases, however, including in Long COVID, fibrinogen polymerise into an anomalous amyloid form to create clots are resistant normal fibrinolysis and we refer as fibrinaloid microclots. These be detected fluorogenic stain thioflavin T. We describe automated microscopic technique for quantification of microclot formation, which also allows kinetics their formation aggregation recorded. here show recombinant nattokinase effective at degrading microclots vitro . This adds otherwise largely anecdotal evidence, review, might anticipated have value part therapeutic treatments individuals COVID related disorders involve

Language: Английский

Citations

6
Viroids, Satellite RNAs and Prions: Folding of Nucleic Acids and Misfolding of Proteins DOI Creative Commons
Gerhard Steger,

Detlev Riesner,

Stanley B. Prusiner

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 360 - 360

Published: Feb. 26, 2024

Theodor (“Ted”) Otto Diener (* 28 February 1921 in Zürich, Switzerland; † March 2023 Beltsville, MD, USA) pioneered research on viroids while working at the Plant Virology Laboratory, Agricultural Research Service, USDA, Beltsville. He coined name viroid and defined viroids’ important features like infectivity of naked single-stranded RNA without protein-coding capacity. During scientific meetings 1970s 1980s, were often discussed conferences together with other “subviral pathogens”. This term includes what are now called satellite RNAs prions. Satellite depend a helper virus have linear or, case virusoids, circular genomes. Prions, proteinaceous infectious particles, agents scrapie, kuru some diseases. Many RNAs, viroids, non-coding exert their function by thermodynamically or kinetically controlled folding, prions solely host-encoded proteins that cause disease misfolding, aggregation transmission conformations into prion isoforms. In this memorial, we will recall work Ted subviral pathogens.

Language: Английский

Citations

2
Redesign of a thioflavin-T-binding protein with a flat β-sheet to evaluate a thioflavin-T-derived photocatalyst with enhanced affinity DOI

Yuina Miura,

Sae Namioka,

Atsushi Iwai

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 269, P. 131992 - 131992

Published: April 30, 2024

Language: Английский

Citations

1
A targetable N-terminal motif orchestrates α-Synuclein oligomer to fibril conversion DOI Open Access
Jaime Santos, Jorge Cuéllar, Irantzu Pallarès

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 10, 2023

ABSTRACT Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson’s disease. However, the development oligomer-targeting therapeutics is constrained by our limited knowledge their structure and molecular determinants driving conversion to fibrils. PSMα3 a nanomolar peptide binder oligomers that inhibits blocking oligomer fibril conversion. Here, we investigate binding discover mechanistic basis this protective activity. We find selectively targets an N-terminal motif (residues 36-61) populates distinct conformation monomeric oligomeric states. This region plays pivotal role conversion, as its absence renders central NAC domain insufficient prompt structural transition. The hereditary mutation G51D, associated with early-onset disease, causes conformational fluctuation region, leading delayed accumulation resistant remodeling chaperones. Overall, findings unveil new targetable oligomers, advance comprehension amyloid reveal facet pathogenic mutations.

Language: Английский

Citations

3
Cryo-EM reconstruction of helical polymers: Beyond the simple cases DOI
Mark A. B. Kreutzberger, Ravi R. Sonani, Edward H. Egelman

et al.

Quarterly Reviews of Biophysics, Journal Year: 2024, Volume and Issue: 57

Published: Jan. 1, 2024

Helices are one of the most frequently encountered symmetries in biological assemblies. Helical symmetry has been exploited electron microscopic studies as a limited number filament images, principle, can provide all information needed to do three-dimensional reconstruction polymer. Over past 25 years, reconstructions helical polymers from cryo-EM images have shifted completely Fourier-Bessel methods single-particle approaches. The approaches allowed people surmount problem that very few crystalline order, and despite flexibility heterogeneity present these polymers, reaching resolution where accurate atomic models be built now become standard. While determining correct may simple for something like F-actin, many other particularly those formed small peptides, it much more challenging. This review discusses why determination problematic, trial-and-error still best approach. Studies macromolecular assemblies, such icosahedral capsids, usually found not imposing leads great reduction while at same time revealing possibly interesting asymmetric features. We show certain assemblies sometimes lead greatly improved resolution. Further, case supercoiled flagellar filaments bacteria archaea, we imposition only wrong, but is necessary, obscures mechanisms whereby supercoil.

Language: Английский

Citations

0