Liquid–liquid phase separation of type II diabetes-associated IAPP initiates hydrogelation and aggregation

Although it is known that RNA undergoes liquid--liquid phase separation (LLPS), the interplay between the molecular driving forces and the emergent features of the condensates, such as their morphologies and dynamical properties, are not well understood. We develop a coarse-grained model to investigate the phase separation of trinucleotide repeat RNAs, which are implicated in neurological disorders such as Huntington disease and amyotrophic lateral sclerosis. After establishing that the simulations reproduce key experimental findings (length and concentration dependence of the phase transition in (CAG)n repeats), we show that once recruited inside the liquid droplets, the monomers transition from hairpin-like structures to extended states. Interactions between the monomers in the condensates result in the formation of an intricate and dense intermolecular network, which severely restrains the fluctuation and mobility of the RNAs inside large droplets. In the largest densely packed high viscosity droplets, the mobility of RNA chains is best characterized by reptation, reminiscent of the dynamics in polymer melts.

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“…Given sufficient time, the large droplets could potentially undergo subsequent maturation through a sol-gel transition. 20, 45–54…”

Section: Resultsmentioning

confidence: 99%

Condensates in RNA Repeat Sequences are Heterogeneously Organized and Exhibit Reptation-like Dynamics

Nguyên

Hori

Thirumalai

2021

Preprint

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“…Other amyloid-associated proteins also undergo phase separation, at least in vitro (Elbaum-Garfinkle, 2019). For example, liquid-liquid phase separation of IAPP is catalyzed by the air-water-interface (Pytowski et al, 2020). Interestingly, Comparison with the non-fibrillogenic rat IAPP revealed that phase separation does not require the presence of the highly amyloidogenic region (residue 20-29), but hydrogelation and aggregation do (Pytowski et al, 2020).…”

Section: Roles Of Flanking Regions In Protein Functionmentioning

confidence: 99%

“…For example, liquid-liquid phase separation of IAPP is catalyzed by the air-water-interface (Pytowski et al, 2020). Interestingly, Comparison with the non-fibrillogenic rat IAPP revealed that phase separation does not require the presence of the highly amyloidogenic region (residue 20-29), but hydrogelation and aggregation do (Pytowski et al, 2020). The prion-like functional amyloid Sup35 also undergoes phase separation, generating protein-specific environmental responses.…”

Section: Roles Of Flanking Regions In Protein Functionmentioning

confidence: 99%

Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins

2020

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Amyloid proteins are involved in many neurodegenerative disorders such as Alzheimer’s disease [Tau, Amyloid β (Aβ)], Parkinson’s disease [alpha-synuclein (αSyn)], and amyotrophic lateral sclerosis (TDP-43). Driven by the early observation of the presence of ordered structure within amyloid fibrils and the potential to develop inhibitors of their formation, a major goal of the amyloid field has been to elucidate the structure of the amyloid fold at atomic resolution. This has now been achieved for a wide variety of sequences using solid-state NMR, microcrystallography, X-ray fiber diffraction and cryo-electron microscopy. These studies, together with in silico methods able to predict aggregation-prone regions (APRs) in protein sequences, have provided a wealth of information about the ordered fibril cores that comprise the amyloid fold. Structural and kinetic analyses have also shown that amyloidogenic proteins often contain less well-ordered sequences outside of the amyloid core (termed here as flanking regions) that modulate function, toxicity and/or aggregation rates. These flanking regions, which often form a dynamically disordered “fuzzy coat” around the fibril core, have been shown to play key parts in the physiological roles of functional amyloids, including the binding of RNA and in phase separation. They are also the mediators of chaperone binding and membrane binding/disruption in toxic amyloid assemblies. Here, we review the role of flanking regions in different proteins spanning both functional amyloid and amyloid in disease, in the context of their role in aggregation, toxicity and cellular (dys)function. Understanding the properties of these regions could provide new opportunities to target disease-related aggregation without disturbing critical biological functions.

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“…Given sufficient time, the large droplets could potentially undergo subsequent maturation through a sol-gel transition. 20,[44][45][46][47][48][49][50][51][52][53] To probe the jamming dynamics of RNAs inside large droplets, we calculated the MSDs for each nucleotide in the RNA chain (Fig. 6c).…”

Section: Monomer Dynamics Inside the Condensates Is Sluggish: Evidencmentioning

confidence: 99%

Condensates in RNA Repeat Sequences are Heterogeneously Organized and Exhibit Reptation-like Dynamics

Nguyên

Hori

Thirumalai

2021

Preprint

View full text Add to dashboard Cite

Although it is known that RNA undergoes liquid–liquid phase separation (LLPS), the interplay between the molecular driving forces and the emergent features of the condensates, such as their morphologies and dynamical properties, is not well understood. We introduce a coarse-grained model to simulate phase separation of trinucleotide repeat RNAs, which are implicated in neurological disorders such as Huntington disease and amyotrophic lateral sclerosis. After establishing that the simulations reproduce key experimental findings (length and concentration dependence of the phase transition in (CAG)n repeats), we show that once recruited inside the liquid droplets, the monomers transition from hairpin-like structures to extended states. Interactions between the monomers in the condensates result in the formation of an intricate and dense intermolecular network, which severely restrains the fluctuations and mobilities of the RNAs inside large droplets. In the largest densely packed high viscosity droplets, the mobility of RNA chains is best characterized by reptation, reminiscent of the dynamics in polymer melts.

show abstract

Liquid–liquid phase separation of type II diabetes-associated IAPP initiates hydrogelation and aggregation

Cited by 77 publications

References 41 publications

Condensates in RNA Repeat Sequences are Heterogeneously Organized and Exhibit Reptation-like Dynamics

Condensates in RNA Repeat Sequences are Heterogeneously Organized and Exhibit Reptation-like Dynamics

Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins

Condensates in RNA Repeat Sequences are Heterogeneously Organized and Exhibit Reptation-like Dynamics

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