Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage DOI Creative Commons
Sonia Ciudad, Eduard Puig, Thomas Botzanowski

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: June 15, 2020

Abstract Formation of amyloid-beta (Aβ) oligomer pores in the membrane neurons has been proposed to explain neurotoxicity Alzheimerʼs disease (AD). Here, we present three-dimensional structure an Aβ formed a mimicking environment, namely Aβ(1-42) tetramer, which comprises six stranded β-sheet core. The two faces core are hydrophobic and surrounded by membrane-mimicking environment while edges hydrophilic solvent-exposed. By increasing concentration sample, octamers also formed, made tetramers facing each other forming β-sandwich structure. Notably, inserted into lipid bilayers as well-defined pores. To establish structure-membrane activity relationships, molecular dynamics simulations were carried out. These studies revealed mechanism disruption water permeation occurred through lipid-stabilized mediated residues located on β-sheets oligomers.

Language: Английский

Interrogating Amyloid Aggregates using Fluorescent Probes DOI
Amir Aliyan, Nathan P. Cook, Ángel A. Martí

et al.

Chemical Reviews, Journal Year: 2019, Volume and Issue: 119(23), P. 11819 - 11856

Published: Nov. 1, 2019

Amyloids are a broad class of proteins and peptides that can misfold assemble into long unbranched fibrils with cross-β conformation. These misfolding aggregation events associated the onset variety human diseases, among them, Alzheimer's disease, Parkinson's Huntington disease. Our understanding amyloids has been greatly supported by fluorescent molecular probes, such as thioflavin-T, which shows an increase in fluorescence emission upon binding to fibrillar aggregates. Since first application thioflavin-T amyloid studies nearly 30 years ago, many probes have emerged exhibiting responses amyloids, intensity changes, shifts maxima, variations lifetimes, others. shed light on topics including kinetics aggregation, effectiveness inhibitors, elucidation sites structures, staining aggregates vitro, ex vivo, vivo. In this Review, we discuss design, properties, photoactive used study well challenges faced current techniques, novel approaches emerging address these challenges.

Language: Английский

Citations

236
Cryo-EM structures of four polymorphic TDP-43 amyloid cores DOI
Qin Cao, David R. Boyer, M.R. Sawaya

et al.

Nature Structural & Molecular Biology, Journal Year: 2019, Volume and Issue: 26(7), P. 619 - 627

Published: June 24, 2019

Language: Английский

Citations

230
Cryo-EM structures of tau filaments DOI
Sjors H. W. Scheres, Wenjuan Zhang, Benjamin Falcon

et al.

Current Opinion in Structural Biology, Journal Year: 2020, Volume and Issue: 64, P. 17 - 25

Published: June 27, 2020

Language: Английский

Citations

225
Mass Spectrometry-Based Protein Footprinting for Higher-Order Structure Analysis: Fundamentals and Applications DOI
Xiaoran Roger Liu, Mengru Zhang, Michael L. Gross

et al.

Chemical Reviews, Journal Year: 2020, Volume and Issue: 120(10), P. 4355 - 4454

Published: April 22, 2020

Proteins adopt different higher-order structures (HOS) to enable their unique biological functions. Understanding the complexities of protein and dynamics requires integrated approaches, where mass spectrometry (MS) is now positioned play a key role. One those approaches footprinting. Although initial demonstration footprinting was for HOS determination protein/nucleic acid binding, concept later adapted MS-based analysis, through which covalent labeling "mark" solvent accessible surface area (SASA) proteins reflect HOS. Hydrogen-deuterium exchange (HDX), deuterium in D2O replaces hydrogen backbone amides, most common example Its advantage that footprint reflects SASA bonding, whereas one drawback reversible. Another slow irreversible functional groups on amino side chains by targeted reagents with high specificity, probing structural changes at selected sites. A third approach reactions fast, species are highly reactive broadly several residue time scale submilliseconds. All these combine constitute problem-solving toolbox enables as valuable tool elucidation. As there has been growing need both academia industry owing its throughput capability, prompt availability, spatial resolution, we present summary history, descriptions, principles, mechanisms, applications approaches. Moreover, highlighted according questions they can answer. This review intended tutorial elucidation reference investigators seeking address science.

Language: Английский

Citations

224
Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage DOI Creative Commons
Sonia Ciudad, Eduard Puig, Thomas Botzanowski

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: June 15, 2020

Abstract Formation of amyloid-beta (Aβ) oligomer pores in the membrane neurons has been proposed to explain neurotoxicity Alzheimerʼs disease (AD). Here, we present three-dimensional structure an Aβ formed a mimicking environment, namely Aβ(1-42) tetramer, which comprises six stranded β-sheet core. The two faces core are hydrophobic and surrounded by membrane-mimicking environment while edges hydrophilic solvent-exposed. By increasing concentration sample, octamers also formed, made tetramers facing each other forming β-sandwich structure. Notably, inserted into lipid bilayers as well-defined pores. To establish structure-membrane activity relationships, molecular dynamics simulations were carried out. These studies revealed mechanism disruption water permeation occurred through lipid-stabilized mediated residues located on β-sheets oligomers.

Language: Английский

Citations

204