Sequence Determines the Switch in the Fibril Forming Regions in the Low-Complexity FUS Protein and Its Variants

Kumar, Abhinaw; Chakraborty, Debayan; Mugnai, Mauro L.; Straub, John E.; Thirumalai, D.

doi:10.1021/acs.jpclett.1c02310

Cited by 25 publications

(87 citation statements)

References 44 publications

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“…These molecular polymorphisms are assumed to be derived from differences in the number, relative orientation, and internal substructure of the protofilaments. Recent simulation studies have shown that the sequence-specific conformational heterogeneities of monomer ensembles are crucially associated with their aggregation propensities and the fibril polymorphisms can be caused by changes in the population of fibril-like states in the monomeric structures [ 56 , 57 ].…”

Section: Structural Polymorphism Of Amyloid Fibrilsmentioning

confidence: 99%

Conformational Variability of Amyloid-β and the Morphological Diversity of Its Aggregates

Yagi-Utsumi

Kato

2022

Molecules

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Protein folding is the most fundamental and universal example of biomolecular self-organization and is characterized as an intramolecular process. In contrast, amyloidogenic proteins can interact with one another, leading to protein aggregation. The energy landscape of amyloid fibril formation is characterized by many minima for different competing low-energy structures and, therefore, is much more enigmatic than that of multiple folding pathways. Thus, to understand the entire energy landscape of protein aggregation, it is important to elucidate the full picture of conformational changes and polymorphisms of amyloidogenic proteins. This review provides an overview of the conformational diversity of amyloid-β (Aβ) characterized from experimental and theoretical approaches. Aβ exhibits a high degree of conformational variability upon transiently interacting with various binding molecules in an unstructured conformation in a solution, forming an α-helical intermediate conformation on the membrane and undergoing a structural transition to the β-conformation of amyloid fibrils. This review also outlines the structural polymorphism of Aβ amyloid fibrils depending on environmental factors. A comprehensive understanding of the energy landscape of amyloid formation considering various environmental factors will promote drug discovery and therapeutic strategies by controlling the fibril formation pathway and targeting the consequent morphology of aggregated structures.

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Section: Structural Polymorphism Of Amyloid Fibrilsmentioning

confidence: 99%

Conformational Variability of Amyloid-β and the Morphological Diversity of Its Aggregates

Yagi-Utsumi

Kato

2022

Molecules

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“…It not only accounts for the possibility of fibril polymorphism, but also provides a basis for understanding the aggregation propensities of different peptide sequences. 29,32…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…It not only accounts for the possibility of fibril polymorphism, but also provides a basis for understanding the aggregation propensities of different peptide sequences. 29,32 The Aβ40 and Aβ42 sequences, which are the major isoforms implicated in AD, behave like intrinsically disordered proteins in their monomeric forms, 31,33,34 which is manifested by a lack of persistent secondary structures. Hence, a microscopic characterization of their conformational ensembles is a challenging task.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, our work, 29 underscores the importance of quantitatively characterizing the N * states present within the monomer conformational ensemble of assembly-competent IDPs in order to provide a microscopic basis for protein aggregation. 29,32 Here, we construct the free energy landscapes of Aβ40 and Aβ42 using simulations of the SOP-IDP model. The landscapes exhibit a pronounced bias towards the disordered random coil ground state, rationalizing why much of the thermodynamic ensemble-averages are reminiscent of random-coils.…”

Section: Introductionmentioning

confidence: 99%

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Energy landscapes of Aβ monomers are sculpted in accordance with Ostwald’s rule of stages

Chakraborty

Straub

Thirumalai

2022

Preprint

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The transition from a disordered to an assembly-competent and sparsely populated monomeric state (N*) in amyloidogenic sequences is a crucial event in the aggregation cascade. Using a well-calibrated model for Intrinsically Disordered Proteins (IDPs),we show that the N* states, which bear considerable resemblance to distinct polymorphic fibril structures found in experiments, not only appear as excitations on the monomer free energy landscapes of Aβ40 and Aβ42 but also initiate the aggregation cascade. Interestingly, for Aβ42, the transitions to the different N* states are in accord with Ostwald's rule of stages, with the least stable structures forming ahead of thermodynamically favored structures, which appear only on longer time-scales. Despite having similar topographies, the Aβ40 and Aβ42 monomer landscapes exhibit different extent of ruggedness, particularly in the vicinity of N* states, which we show have profound implications in dictating the intramolecular diffusion rates, and subsequent self-assembly into higher order structures. The network of connected kinetic states, which for Aβ42 is considerably more complex than for Aβ40, shows that the most favored dimerization routes proceed via the N* states. Direct transition between the disordered ground states within the monomer and dimer basins is less likely. The Ostwald's rule of stages holds widely, qualitatively explaining the unusual features in other fibril forming IDPs, such as Fused in Sarcoma (FUS). Similarly, the N* theory accounts for dimer formation in small disordered polyglutamine peptides, implicated in the Huntington disease.

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Conformational fluctuations and phases in fused in sarcoma (FUS) low‐complexity domain

et al. 2023

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The well‐known phenomenon of phase separation in synthetic polymers and proteins has become a major topic in biophysics because it has been invoked as a mechanism of compartment formation in cells, without the need for membranes. Most of the coacervates (or condensates) are composed of Intrinsically Disordered Proteins (IDPs) or regions that are structureless, often in interaction with RNA and DNA. One of the more intriguing IDPs is the 526‐residue RNA‐binding protein, Fused in Sarcoma (FUS), whose monomer conformations and condensates exhibit unusual behavior that are sensitive to solution conditions. By focussing principally on the N‐terminus low‐complexity domain (FUS‐LC comprising residues 1–214) and other truncations, we rationalize the findings of solid‐state NMR experiments, which show that FUS‐LC adopts a non‐polymorphic fibril structure (core‐1) involving residues 39–95, flanked by fuzzy coats on both the N‐ and C‐terminal ends. An alternate structure (core‐2), whose free energy is comparable to core‐1, emerges only in the truncated construct (residues 110–214). Both core‐1 and core‐2 fibrils are stabilized by a Tyrosine ladder as well as hydrophilic interactions. The morphologies (gels, fibrils, and glass‐like) adopted by FUS seem to vary greatly, depending on the experimental conditions. The effect of phosphorylation is site‐specific. Simulations show that phosphorylation of residues within the fibril has a greater destabilization effect than residues that are outside the fibril region, which accords well with experiments. Many of the peculiarities associated with FUS may also be shared by other IDPs, such as TDP43 and hnRNPA2. We outline a number of problems for which there is no clear molecular explanation.

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Sequence Determines the Switch in the Fibril Forming Regions in the Low-Complexity FUS Protein and Its Variants

Cited by 25 publications

References 44 publications

Conformational Variability of Amyloid-β and the Morphological Diversity of Its Aggregates

Conformational Variability of Amyloid-β and the Morphological Diversity of Its Aggregates

Energy landscapes of Aβ monomers are sculpted in accordance with Ostwald’s rule of stages

Conformational fluctuations and phases in fused in sarcoma (FUS) low‐complexity domain

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