Two timescales control the creation of large protein aggregates in cells

Miangolarra, Ander Movilla; Duperray-Susini, Aléria; Coppey, Mathieu; Castellana, Michele

doi:10.1016/j.bpj.2021.04.032

Cited by 5 publications

(4 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…III for the equilibrium conditions. This partial equilibrium holds when the molecular transitions among assemblies are slow compared to phase separation, i.e., the system is reaction-limited [57,58]. This limit applies particularly well to molecular assemblies involving biological enzymes [59].…”

Section: Kinetic Theory Of Assembly At Phase Equilibriummentioning

confidence: 99%

“…This partial equilibrium holds when the molecular transitions among assemblies are slow compared to phase separation. This case is often referred to reaction-limited [57, 58] and applies particularly well to molecular assemblies involving biological enzymes [59]. For simplicity, we present the kinetic theory and discuss the results for two coexisting phases.…”

Section: Kinetic Theory Of Assembly At Phase Equilibriummentioning

confidence: 99%

See 1 more Smart Citation

The interplay between biomolecular assembly and phase separation

Bartolucci

Michaels

Weber

2023

Preprint

View full text Add to dashboard Cite

Interactions among proteins in living cells can lead to molecular assemblies of different sizes and large-scale coexisting phases formed via phase separation. Both are essential for the spatial organization of cells and for regulating biological function and dysfunction. A key challenge is understanding the interplay between molecular assembly and phase separation. However, a corresponding theoretical framework that relies on thermodynamic principles is lacking. Here, we present a non-equilibrium thermodynamic theory for a multi-component mixture that contains assemblies of different sizes, which can form, dissolve, and phase-separate from the solvent. We show that the size distributions of assemblies differ between the phases and that the dense phase can gelate. Moreover, we unravel the mechanisms involved in growth and compositional changes of the coexisting phases during assembly kinetics. Our theory can explain how molecular assembly is intertwined with phase separation, and our results are consistent with recent experimental observations on protein phase separation.

show abstract

Section: Kinetic Theory Of Assembly At Phase Equilibriummentioning

confidence: 99%

Section: Kinetic Theory Of Assembly At Phase Equilibriummentioning

confidence: 99%

The interplay between biomolecular assembly and phase separation

Bartolucci

Michaels

Weber

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Instead, we assume that particles exist in either an active or inactive state, and can only form clusters in the active state. One motivation for the 3D model is a recent study of the optogenetic protein CRY2olig, which oligomerizes (forms small clusters) in the presence of blue light [ 55 ]. (In this particular study, the authors explore both theoretically and experimentally the effects of obstacles on the formation of large 3D protein clusters via the diffusion-limited aggregation of oligomers.)…”

Section: Introductionmentioning

confidence: 99%

Asymptotic analysis of particle cluster formation in the presence of anchoring sites

Bressloff

2024

Eur. Phys. J. E

View full text Add to dashboard Cite

The aggregation or clustering of proteins and other macromolecules plays an important role in the formation of large-scale molecular assemblies within cell membranes. Examples of such assemblies include lipid rafts, and postsynaptic domains (PSDs) at excitatory and inhibitory synapses in neurons. PSDs are rich in scaffolding proteins that can transiently trap transmembrane neurotransmitter receptors, thus localizing them at specific spatial positions. Hence, PSDs play a key role in determining the strength of synaptic connections and their regulation during learning and memory. Recently, a two-dimensional (2D) diffusion-mediated aggregation model of PSD formation has been developed in which the spatial locations of the clusters are determined by a set of fixed anchoring sites. The system is kept out of equilibrium by the recycling of particles between the cell membrane and interior. This results in a stationary distribution consisting of multiple clusters, whose average size can be determined using an effective mean-field description of the particle concentration around each anchored cluster. In this paper, we derive corrections to the mean-field approximation by applying the theory of diffusion in singularly perturbed domains. The latter is a powerful analytical method for solving two-dimensional (2D) and three-dimensional (3D) diffusion problems in domains where small holes or perforations have been removed from the interior. Applications range from modeling intracellular diffusion, where interior holes could represent subcellular structures such as organelles or biological condensates, to tracking the spread of chemical pollutants or heat from localized sources. In this paper, we take the bounded domain to be the cell membrane and the holes to represent anchored clusters. The analysis proceeds by partitioning the membrane into a set of inner regions around each cluster, and an outer region where mean-field interactions occur. Asymptotically matching the inner and outer stationary solutions generates an asymptotic expansion of the particle concentration, which includes higher-order corrections to mean-field theory that depend on the positions of the clusters and the boundary of the domain. Motivated by a recent study of light-activated protein oligomerization in cells, we also develop the analogous theory for cluster formation in a three-dimensional (3D) domain. The details of the asymptotic analysis differ from the 2D case due to the contrasting singularity structure of 2D and 3D Green’s functions. Graphical abstract 2D model of diffusion-based protein cluster formation in the presence of anchoring cites and particle recycling. a A set of N anchoring sites at positions $${\textbf{x}}_j$$ x j , $$j=1,\ldots ,N$$ j = 1 , … , N , in a bounded domain $$\Omega $$ Ω . b Diffusing particles accumulate at the anchoring sites resulting in the formation of particle aggregates or clusters $${{\mathcal {U}}}_j$$ U j . c The clusters are dynamically maintained by a combination of lateral diffusion outside the clusters and particle recycling

show abstract

“…Moore's law 44 up to some extent has helped in surpass this limitation. The aggregation process is usually of the order of hour timescale phenomenon, 45 and all‐atom MD is usually of the timescale of nanoseconds 36 . Yet, it significantly describes what drives the aggregation of monomeric protein at an early stage or, more specifically, the transient regions towards which therapeutic agents should be targeted.…”

Section: Introductionmentioning

confidence: 99%

Natural compound plumbagin based inhibition of hIAPP revealed by Markov state models based on MD data along with experimental validations

Nabi,

Ahmad,

Khan

et al. 2024

Proteins

View full text Add to dashboard Cite

Human islet amyloid polypeptide (amylin or hIAPP) is a 37 residue hormone co‐secreted with insulin from β cells of the pancreas. In patients suffering from type‐2 diabetes, amylin self‐assembles into amyloid fibrils, ultimately leading to the death of the pancreatic cells. However, a research gap exists in preventing and treating such amyloidosis. Plumbagin, a natural compound, has previously been demonstrated to have inhibitory potential against insulin amyloidosis. Our investigation unveils collapsible regions within hIAPP that, upon collapse, facilitates hydrophobic and pi‐pi interactions, ultimately leading to aggregation. Intriguingly plumbagin exhibits the ability to bind these specific collapsible regions, thereby impeding the aforementioned interactions that would otherwise drive hIAPP aggregation. We have used atomistic molecular dynamics approach to determine secondary structural changes. MSM shows metastable states forming native like hIAPP structure in presence of PGN. Our in silico results concur with in vitro results. The ThT assay revealed a striking 50% decrease in fluorescence intensity at a 1:1 ratio of hIAPP to Plumbagin. This finding suggests a significant inhibition of amyloid fibril formation by plumbagin, as ThT fluorescence directly correlates with the presence of these fibrils. Further TEM images revealed disappearance of hIAPP fibrils in plumbagin pre‐treated hIAPP samples. Also, we have shown that plumbagin disrupts the intermolecular hydrogen bonding in hIAPP fibrils leading to an increase in the average beta strand spacing, thereby causing disaggregation of pre‐formed fibrils demonstrating overall disruption of the aggregation machinery of hIAPP. Our work is the first to report a detailed atomistic simulation of 22 μs for hIAPP. Overall, our studies put plumbagin as a potential candidate for both preventive and therapeutic candidate for hIAPP amyloidosis.

show abstract

Two timescales control the creation of large protein aggregates in cells

Cited by 5 publications

References 21 publications

The interplay between biomolecular assembly and phase separation

The interplay between biomolecular assembly and phase separation

Asymptotic analysis of particle cluster formation in the presence of anchoring sites

Natural compound plumbagin based inhibition of hIAPP revealed by Markov state models based on MD data along with experimental validations

Contact Info

Product

Resources

About