Biomolecular condensates can both accelerate and suppress aggregation of α-synuclein DOI Creative Commons
Wojciech P. Lipiński, Brent S. Visser, Irina Robu

et al.

Science Advances, Journal Year: 2022, Volume and Issue: 8(48)

Published: Dec. 2, 2022

Biomolecular condensates present in cells can fundamentally affect the aggregation of amyloidogenic proteins and play a role regulation this process. While liquid-liquid phase separation by themselves act as an alternative nucleation pathway, interaction partly disordered aggregation-prone with preexisting that localization centers could be far more general mechanism altering their behavior. Here, we show so-called host biomolecular both accelerate slow down amyloid formation. We study protein α-synuclein two truncated variants presence three types composed nonaggregating peptides, RNA, or ATP. Our results demonstrate markedly speed up formation when localize to interface. However, also significantly suppress sequestering stabilizing proteins, thereby providing living possible protection against

Language: Английский

Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing DOI
Simon Alberti, Anthony A. Hyman

Nature Reviews Molecular Cell Biology, Journal Year: 2021, Volume and Issue: 22(3), P. 196 - 213

Published: Jan. 28, 2021

Language: Английский

Citations

877
Liquid–liquid phase separation in human health and diseases DOI Creative Commons
Bin Wang, Lei Zhang, Tong Dai

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Aug. 1, 2021

Abstract Emerging evidence suggests that liquid–liquid phase separation (LLPS) represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells (also known as biomolecular condensates or droplets). Recent studies have revealed evidences indicate LLPS plays role human health diseases. In this review, we describe our current understanding summarize its physiological functions. We further development Additionally, review recently developed methods for studying LLPS. Although research is infancy—but fast-growing—it clear an essential pathophysiological conditions. This highlights need overview recent advances field to translate knowledge regarding into therapeutic discoveries.

Language: Английский

Citations

465
Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force DOI Creative Commons
Aurélie Zbinden, Manuela Pérez‐Berlanga, Pierre De Rossi

et al.

Developmental Cell, Journal Year: 2020, Volume and Issue: 55(1), P. 45 - 68

Published: Oct. 1, 2020

Language: Английский

Citations

386
Beyond aggregation: Pathological phase transitions in neurodegenerative disease DOI
Cécile Mathieu, Rohit V. Pappu, J. Paul Taylor

et al.

Science, Journal Year: 2020, Volume and Issue: 370(6512), P. 56 - 60

Published: Oct. 2, 2020

Over the past decade, phase transitions have emerged as a fundamental mechanism of cellular organization. In parallel, wealth evidence has accrued indicating that aberrations in are early events pathogenesis several neurodegenerative diseases. We review key defects at multiple levels, from transition individual proteins to dynamic behavior complex, multicomponent condensates neurodegeneration. also highlight two concepts, dynamical arrest and heterotypic buffering, understanding how pathological relate pleiotropic functions accrual proteinaceous deposits end-stage disease. These insights not only illuminate disease etiology but likely guide development therapeutic interventions restore homeostasis.

Language: Английский

Citations

342
Accurate model of liquid–liquid phase behavior of intrinsically disordered proteins from optimization of single-chain properties DOI
Giulio Tesei, Thea K. Schulze, Ramón Crehuet

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(44)

Published: Oct. 29, 2021

Significance Cells may compartmentalize proteins via a demixing process known as liquid–liquid phase separation (LLPS), which is often driven by intrinsically disordered (IDPs) and regions. Protein condensates arising from LLPS develop into insoluble protein aggregates, in neurodegenerative diseases cancer. Understanding the of formation, dissolution, aging requires models that accurately capture underpinning interactions at residue level. In this work, we leverage data biophysical experiments on IDPs dilute solution to sequence-dependent model predicts conformational behavior diverse unrelated sequences with good accuracy. Using model, gain insight coupling between chain compaction propensity.

Language: Английский

Citations

294
Widespread occurrence of the droplet state of proteins in the human proteome DOI Creative Commons
Maarten C. Hardenberg, Attila Horváth,

Viktor Ambrus

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(52), P. 33254 - 33262

Published: Dec. 14, 2020

Significance Liquid–liquid phase separation of proteins results in biomolecular condensates, which contribute to the organization cellular matter into membraneless organelles. It is still unclear, however, whether these condensates represent a common state proteins. Here, based on biophysical principles driving separation, we report proteome-wide ranking according their propensity condensate droplet state. We analyze two mechanisms for formation—driver can spontaneously separate, while client require additional components. conclude that state, as native and amyloid states, fundamental proteins, with most expected be capable undergoing liquid–liquid via either mechanisms.

Language: Английский

Citations

287
Peptide-Based Supramolecular Systems Chemistry DOI

Fahmeed K. Sheehan,

Deborah Sementa, Ankit Jain

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(22), P. 13869 - 13914

Published: Sept. 14, 2021

Peptide-based supramolecular systems chemistry seeks to mimic the ability of life forms use conserved sets building blocks and chemical reactions achieve a bewildering array functions. Building on design principles for short peptide-based nanomaterials with properties, such as self-assembly, recognition, catalysis, actuation, are increasingly available. is starting address far greater challenge systems-level access complex functions that emerge when multiple interactions coordinated integrated. We discuss key features relevant design, including regulating order disorder, development active adaptive by considering kinetic thermodynamic aspects combinatorial dynamic covalent noncovalent interactions. Finally, we how structural concepts, preorganization induced fit, critical develop materials tunable photonic, electronic, catalytic properties. highlight examples where combined, resulting in display properties cannot be achieved without this level integration.

Language: Английский

Citations

287
Evaluation of Peptide/Protein Self-Assembly and Aggregation by Spectroscopic Methods DOI Creative Commons
María Florencia Pignataro, María Georgina Herrera, Verónica I. Dodero

et al.

Molecules, Journal Year: 2020, Volume and Issue: 25(20), P. 4854 - 4854

Published: Oct. 21, 2020

The self-assembly of proteins is an essential process for a variety cellular functions including cell respiration, mobility and division. On the other hand, protein or peptide misfolding aggregation related to development Parkinson’s disease Alzheimer’s disease, among aggregopathies. As consequence, significant research efforts are directed towards understanding this process. In review, we focused on use UV-Visible Absorption Spectroscopy, Fluorescence Spectroscopy Circular Dichroism evaluate self-organization peptides in solution. These spectroscopic techniques commonly available most chemistry biochemistry laboratories, together they powerful approach initial as well routine evaluation under different environmental stimulus. Furthermore, these even suitable studying complex systems like those food industry pharmaceutical formulations, providing overall idea folding, self-assembly, processes, which challenging obtain with high-resolution methods. Here, compiled discussed selected examples, our results that helped us better understand aggregation. We put particular emphasis basic description methods experimental considerations needed meaningful information, help who just getting into exciting area research. Moreover, review particularly useful out field would improve reproducibility their biomedical experiments, especially while working external Our final aim show power low-resolution translate fundamental knowledge applications.

Language: Английский

Citations

161
Reverse engineering Lewy bodies: how far have we come and how far can we go? DOI

Mohamed Bilal Fares,

Somanath Jagannath,

Hilal A. Lashuel

et al.

Nature reviews. Neuroscience, Journal Year: 2021, Volume and Issue: 22(2), P. 111 - 131

Published: Jan. 11, 2021

Language: Английский

Citations

147
Conformational Dynamics of Intrinsically Disordered Proteins Regulate Biomolecular Condensate Chemistry DOI Creative Commons
Anton Abyzov, Martin Blackledge, Markus Zweckstetter

et al.

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(6), P. 6719 - 6748

Published: Feb. 18, 2022

Motions in biomolecules are critical for biochemical reactions. In cells, many reactions executed inside of biomolecular condensates formed by ultradynamic intrinsically disordered proteins. A deep understanding the conformational dynamics proteins is therefore utmost importance but complicated diverse obstacles. Here we review emerging data on motions liquidlike condensates. We discuss how liquid-liquid phase separation modulates internal across a wide range time and length scales. further highlight intermolecular interactions that not only drive appear as key determinants changes aging human diseases. The provides framework future studies to reveal regulation condensate chemistry.

Language: Английский

Citations

138