Search

Here, the authors introduce AlphaFold-Metainference, which uses inter-residue distances predicted by AlphaFold to generate structural ensembles of disordered proteins.

FuzDrop predicts the condensation propensity of proteins on the basis of their amino acid sequences. This protocol describes the underlying theory and how to use the results to understand liquid-liquid phase separation and amyloid aggregate formation.

Understanding the chemical mechanisms that govern amyloid deposition — a hallmark of numerous age-related diseases — is crucial for advancing the rational development of protein aggregation inhibitors. Here, the authors report the quantitative aggregation mechanism of medin, the most common localized amyloid in humans, and find it to be much faster compared to well-known pathological amyloids such as amyloid-β (Aβ), tau and α-synuclein.

Authors study links between amyloid secondary nucleation and growth defects, demonstrating these sites on Aβ40/Aβ42 fibrils are rare compared to the number of protein molecules. Re-analysis of published data suggests that defects may also drive secondary nucleation generally.

Michele Vendruscolo and colleagues propose that polyglutamine repeat expansion diseases could be caused by glutaminyl-tRNA depletion, leading to ribosome frameshifting and mistranslation of transcripts with specific characteristics.

Lee et al. show that Ca²⁺ triggers condensates enriched with PDIA6, an ER-resident disulfide isomerase and chaperone, along with other protein disulfide isomerase family proteins and some chaperones that in turn enhance folding of proinsulin.

The formation of protein aggregates is a hallmark of Parkinson’s disease, with small oligomeric species implicated as a major source of toxicity. In this work, Xu et al. determine their mechanism of formation and role in aggregation.

Neurodegenerative disorders remain poorly treated despite their growing disease burden. Here, authors developed a multiplexed screening platform that identified DNAJB6 as a modulator of condensate maturation and suppressor ALS/FTD-linked toxicity.

This Perspective establishes a comprehensive and practical framework to guide intrinsically disordered protein (IDP) ensemble determination, benchmarking and interpretation, as well as proposes a roadmap for IDP ensemble determination, uncertainty quantification and actionable benchmarking strategies.

An optical detection and analysis platform quantifies aggregate density, distribution and size in fluorescently labelled post-mortem human brain tissue.

Ligand-Transformer is a deep learning framework that predicts protein–ligand binding and conformational changes using only sequence and 2D-structure inputs, enabling efficient virtual screening and uncovering mechanisms of drug action.

In this Perspective, Fuxreiter and Vendruscolo discuss the fundamental nature of the droplet and amyloid states of proteins, the regulatory mechanisms controlling their formation, and the cellular functions associated with these condensed states.

An overview of the progress and potential of nanopore-based detection of oligomerizing proteins is presented, covering the latest advances and combination with other emerging technologies including device design, DNA nanostructure tagging and machine learning-enabled signal analysis.

Nixon-Abell et al. show that ANXA11 condensation on lysosomal membranes causes a coupled phase transition of the underlying lipids and mechanical stiffening of the overall ensemble involved in RNP granule-lysosome tethering and co-trafficking.

Cholesterol embedded in lipid membranes strongly promotes the aggregation of Aβ42 that is associated with Alzheimer's disease. Now, a kinetic analysis has shown that the mechanism of action responsible for this effect involves the introduction of a heterogeneous nucleation pathway that enhances the primary nucleation rate of Aβ42 aggregation by up to 20-fold.

An approach based on soft Markov state models is capable of constructing interpretable kinetic ensembles of disordered proteins.

Aggregated forms of α-synuclein are characteristic of Parkinson’s disease. Here the authors show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules: the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein primary nucleation in the aggregation process.

Proteins can self-assemble into functional states, or they can end up as aberrant and sometimes toxic aggregates. Metastable intermediate states are often detected in these processes, and their structural characterization provides vital information about the balance between functional and pathological behavior in living systems.

Protein aggregation causes problems for biotechnology and leads to many fatal human diseases. But a grasp of the physical principles involved enables 'superproteins' to be designed that have exceptional solubilities.

The combination of NMR spectroscopy and statistical mechanics represents a powerful approach to characterize the behavior of macromolecules. Two recent studies demonstrate that the application of this strategy to analyze chemical shift measurements can reveal complex mechanisms of protein regulation.

A stochastic view of allostery is providing quantitative estimates of the energy made available through protein photoswitches.

Mice expressing humanized mutant tau exhibit synaptic loss and behavioral abnormalities in the absence of abnormal tau conformers, suggesting that hyperphosphorylated tau can be pathological, at least in tauopathies caused by tau isoform imbalance.

Posttranslationally modified amino acids are crucial in physiology and drug development as they alter physicochemical properties such as the solubility of proteins. Here the authors describe CamSolPTM, a software that accurately predicts the solubility of proteins containing these residues.

Transient oligomeric species of the amyloid-β peptide (Aβ₄₂) have been identified as key pathogenic agents in Alzheimer’s disease. Here the authors find that the aminosterol trodusquemine enhances Aβ₄₂ aggregation and suppresses Aβ₄₂-induced toxicity by displacing oligomers from cell membranes.

In this work, Kamal, Knox et al develop a high-throughput system to identify small molecules that disrupt amyloid formation by pre-selecting compounds that suppress molecular interactions within the cuticle of the C. elegans pharynx.

Bhardwaj et al., have explored the proteomes of SARS-CoV and SARS-CoV-2, and have demonstrated the amyloid formation of viral proteins, in vitro, through diverse biophysical techniques.

Developing disease-modifying drugs for neurodegenerative diseases has been very challenging. Now a machine learning approach has been used to identify small molecule inhibitors of α-synuclein aggregation, a process implicated in Parkinson’s disease and other synucleinopathies. Compounds that bind to the catalytic sites on the surface of the aggregates were identified and then progressively optimized into secondary nucleation inhibitors.

Molecular chaperones from the Hsp70 family can break up protein aggregates, including amyloids. Here, the authors utilize microfluidic diffusional sizing to assess the mechanism of α-synuclein (αS) disaggregation by the Hsc70–DnaJB1–Apg2 system, and show that single αS molecules are removed directly from the fibril ends.

Fluorescence microscopy and kinetics analyses reveal that Aβ42 oligomers generated through secondary nucleation are responsible for membrane disruption.

Our understanding of the molecular mechanisms underlying pathological protein aggregation remains incomplete. Here, single molecule infrared nanospectroscopy (AFM-IR) offers insight into the structure of Aβ42 oligomeric and fibrillar species and their interaction with an aggregation inhibitor, paving the way for single molecule drug discovery studies.

α-Synuclein is a presynaptic protein whose aberrant aggregation is associated with Parkinson’s disease. Here, the authors show how αSynuclein-induced docking of synaptic vesicles is modulated by the lipid composition changes typically observed in neurodegeneration using an in vitro system.

Protein aggregation and amyloid deposition are associated with a wide range of medical disorders, including Alzheimer's disease and type II diabetes. Studies into the amyloid state are revealing fundamental principles that underlie the maintenance of protein homeostasis, and the origins of aberrant protein behaviour and disease.

Im7 is a small Escherichia coli colicin binding protein that uses a remarkably complex folding pathway. Analysis of the Im7 folding landscape reveals details of the earliest transition state in its folding pathway and indicates that the formation of non-native contacts that result in intermediate folding states is necessary to maintain elements essential to the protein's function.

α-synuclein is a protein whose aberrant aggregation is associated with Parkinson’s disease. Here, Fusco et al.characterize α-synuclein bound to lipid membranes using a combination of solution and solid-state NMR spectroscopy and provide insights into the molecular processes associated with the aggregation of this protein.

Labelling biomolecules to improve the sensitivity of analysis can perturb their interactions. Now, microfluidic and chemical tools have been used to allow simple, sensitive detection of a labelled system to reveal the behaviour of the native and physiologically relevant unlabelled system. The system was used to characterize the solution-phase behaviour of a clinically relevant protein–protein interaction.

Proteins can undergo folding while being translated by the ribosome, and the extent of this folding is influenced by the rate at which amino acids are added to the nascent chain. This study provides a framework for predicting domain folding probabilities as a function of the kinetics of amino-acid addition.

Molecular chaperones are recognized to interfere with protein aggregation, yet the underlying mechanisms are largely unknown. Here, the authors develop a kinetic model that reveals the variety of distinct microscopic mechanisms through which molecular chaperones act to suppress amyloid formation.

A high-resolution structure of an off-pathway misfolded intermediate state of a PDZ domain is now obtained, through a combination of phi-value analysis and computational modeling. The structure reveals that a misfolded intermediate can look quite similar to the native state.

α-synuclein aggregates cause neuronal damage, but their heterogeneity complicates studying their toxic properties. Here, the authors analyze α-synuclein aggregates in vitro and study post-mortem brain samples, providing evidence that small aggregates are the main culprit for neuronal death in Parkinson’s disease.

Aβ42 oligomers are key toxic species associated with protein aggregation; however, the molecular pathways determining the dynamics of oligomer populations have remained unknown. Now, direct measurements of oligomer populations, coupled to theory and computer simulations, define and quantify the dynamics of Aβ42 oligomers formed during amyloid aggregation.