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Local environment in biomolecular condensates modulates enzymatic activity across length scales
Here, the authors show that biomolecular condensates can enhance enzymatic rates by creating distinct solvent environments compared to the surrounding solution, and this emergent property can manifest within assemblies as small as nanometers.
- Marcos Gil-Garcia
- , Ana I. Benítez-Mateos
- & Paolo Arosio
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An adaptive biomolecular condensation response is conserved across environmentally divergent species
Cells must respond to environmental changes. In three fungal species adapted to different temperatures, cellular responses are conserved yet tuned to each organism’s thermal niche, including the formation of adaptive biomolecular condensates.
- Samantha Keyport Kik
- , Dana Christopher
- & D. Allan Drummond
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Article
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Pathogenic mutations of human phosphorylation sites affect protein–protein interactions
Here the authors characterise the impact of phosphorylation site mutations in intrinsically disordered regions (IDRs) on protein-protein interactions, highlighting the critical role of phosphorylation of IDRs in health and disease.
- Trendelina Rrustemi
- , Katrina Meyer
- & Matthias Selbach
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Fuzzy recognition by the prokaryotic transcription factor HigA2 from Vibrio cholerae
Here, the authors dissect the fuzzy interaction between the prokaryote transcription factor HigA2 and its DNA target and show that specific, transient interactions drive specificity despite HigA2 remaining mostly disordered.
- San Hadži
- , Zala Živič
- & Remy Loris
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Halogen doped graphene quantum dots modulate TDP-43 phase separation and aggregation in the nucleus
Modulating amyloid protein phase separation and fibrilization may help in addressing neurodegenerative diseases. This study demonstrates that halogen-doped graphene quantum dots can modulate these processes in TDP-43 in both nucleus and cytoplasm.
- Hong Zhang
- , Huazhang Guo
- & Bin Dai
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Hairpin trimer transition state of amyloid fibril
Amyloid fibrils are ordered protein assemblies implicated in neurodegenerative disease. Here the authors show that hairpin trimers can be transition states of fibril nucleation, explaining how different fibril isoforms may arise from alternative nucleation sites.
- Levent Sari
- , Sofia Bali
- & Milo M. Lin
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Structural basis for autoinhibition by the dephosphorylated regulatory domain of Ycf1
Yeast cadmium factor 1 (Ycf1), a heavy metal and glutathione transporter, is regulated by an intrinsically disordered region called the regulatory domain. In this work, the authors show that this domain controls activity through autoinhibition of the glutathione cavity when it is dephosphorylated.
- Nitesh Kumar Khandelwal
- & Thomas M. Tomasiak
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Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles
X-ray scattering and electron microscopy are used in concert to show that complexes of tubulin oligomers and tau are building blocks of an intervening network that cross-bridge microtubules into bundles with the same linear geometry observed in neurons.
- Phillip A. Kohl
- , Chaeyeon Song
- & Cyrus R. Safinya
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Machine learning predictor PSPire screens for phase-separating proteins lacking intrinsically disordered regions
Here the authors report a machine learning model, PSPire, which integrates both residue-level and structure-level features and outperforms tools in identifying phase-separating proteins lacking intrinsically disordered regions.
- Shuang Hou
- , Jiaojiao Hu
- & Yong Zhang
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Alternative low-populated conformations prompt phase transitions in polyalanine repeat expansions
Here, the authors show that pathogenic mutations in the polyalanine expansions of PHOX2B promote nascent structural conformations that trigger irreversible phase transitions that arrest wild-type PHOX2B, disrupting function.
- Rosa Antón
- , Miguel Á. Treviño
- & Javier Oroz
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Sequence-dependent material properties of biomolecular condensates and their relation to dilute phase conformations
How material properties affect the functional state of biocondensates is a long-standing question. Here the authors demonstrate how such properties are encoded in a disordered protein sequence and can be predicted from dilute phase conformations.
- Dinesh Sundaravadivelu Devarajan
- , Jiahui Wang
- & Jeetain Mittal
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DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2
The function of transcription factors is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains, but the lack of quantitative structural ensemble models prevents their mechanistic decoding. Here, the authors use several methods to demonstrate that DNA binding can lead to complex changes in the IDR ensemble and accessibility on the example of the C-terminal IDR of pioneer factor Sox2.
- Sveinn Bjarnason
- , Jordan A. P. McIvor
- & Pétur O. Heidarsson
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The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12
Here, the authors utilise an integrative approach to characterise the fuzzy heterocomplex between CXCL12 and the fully reduced alarmin HMGB1, highlighting the importance of HMGB1’s acidic IDR to the interaction and with cell surface CXCR4.
- Malisa Vittoria Mantonico
- , Federica De Leo
- & Giovanna Musco
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Heterotypic interactions can drive selective co-condensation of prion-like low-complexity domains of FET proteins and mammalian SWI/SNF complex
Prion-like domains are intrinsically disordered regions found in many RNA- and DNA-binding proteins. Here, the authors show that these domains can drive sequence-specific co-phase separation of chromatin remodeling complex with FET oncofusion proteins.
- Richoo B. Davis
- , Anushka Supakar
- & Priya R. Banerjee
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G-quadruplexes promote the motility in MAZ phase-separated condensates to activate CCND1 expression and contribute to hepatocarcinogenesis
G-quadruplexes (G4s) can recruit transcription factors to activate genes. Here, the authors revealed that G4s drive molecular motility in phase-separated condensates of MAZ and coactivators, leading to activated CCND1 expression in liver cancer.
- Wenmeng Wang
- , Dangdang Li
- & Guangchao Sui
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Endothelial leakiness elicited by amyloid protein aggregation
This study reports endothelial leakiness in vitro, in silico and in vivo, where adherens junctions are disrupted by their exposure to the anionic oligomers and seeds of Alzheimer’s amyloid beta, preceding proinflammatory and pro-oxidative events.
- Yuhuan Li
- , Nengyi Ni
- & Pu Chun Ke
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Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners
Here, the authors investigate the maturation of human respiratory Complex II, uncovering two metastable intermediates of maturation which suggest changes in intrinsic disorder ensure that the assembly steps occur in the correct sequence.
- Pankaj Sharma
- , Elena Maklashina
- & T. M. Iverson
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The juxtamembrane linker of synaptotagmin 1 regulates Ca2+ binding via liquid-liquid phase separation
Synaptotagmin (syt) 1 is a calcium sensor for neuronal exocytosis. Here, the authors show that the juxtamembrane linker of this integral membrane protein negatively regulates its calcium sensing activity by mediating self-association via liquid-liquid phase separation.
- Nikunj Mehta
- , Sayantan Mondal
- & Edwin R. Chapman
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Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif
Drp1 is the master regulator of mitochondrial and peroxisomal fission. Here, the authors show that a C-terminal intrinsically disordered motif, named the CT-SLiM, constitutes an allosteric switch that controls Drp1 structure, assembly, and function.
- Isabel Pérez-Jover
- , Kristy Rochon
- & Rajesh Ramachandran
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Transmembrane coupling of liquid-like protein condensates
Using a freestanding planar lipid membrane system, the authors show that liquid-like protein condensates on one side of a lipid membrane colocalize with those on the opposite side, suggesting a mechanism of information transfer across biological membranes.
- Yohan Lee
- , Sujin Park
- & Jeanne C. Stachowiak
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Label-free identification of protein aggregates using deep learning
The authors use deep learning to detect and segment unlabeled and unaltered protein aggregates in living cells from transmitted-light images. The method provides a way to quantitatively study protein aggregation dynamics in a simple, fast and accurate way.
- Khalid A. Ibrahim
- , Kristin S. Grußmayer
- & Aleksandra Radenovic
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Intra- and inter-molecular regulation by intrinsically-disordered regions governs PUF protein RNA binding
FBF-2 and LST-1 repress gld-1 mRNA expression to maintain C. elegans germline stem cells. The authors show that an intrinsically-disordered region of FBF-2 autoinhibits its RNA binding. LST-1 antagonizes this interaction to promote RNA binding.
- Chen Qiu
- , Zihan Zhang
- & Traci M. Tanaka Hall
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Single-molecule FRET unmasks structural subpopulations and crucial molecular events during FUS low-complexity domain phase separation
Using single-molecule FRET, the authors discover hidden structural subpopulations of the intrinsically disordered prion-like low-complexity domain of FUS and dissect key molecular events that drive dynamic network formation during phase separation.
- Ashish Joshi
- , Anuja Walimbe
- & Samrat Mukhopadhyay
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Local membrane source gathering by p62 body drives autophagosome formation
Phase separated p62 body plays pivotal roles in autophagy. Here, the authors describe a spatial membrane gathering mode by which p62 body functions in autophagosome formation.
- Xuezhao Feng
- , Daxiao Sun
- & Na Mi
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Efficient optical plasmonic tweezer-controlled single-molecule SERS characterization of pH-dependent amylin species in aqueous milieus
Studying rare species in mixtures is challenging. Here, authors utilize on-and-off optical plasmonic trapping to control SERS-active nanocavity to analyse pH-dependent amylin species at single-molecule level, unveiling amyloid aggregation mechanisms.
- Wenhao Fu
- , Huanyu Chi
- & Jinqing Huang
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Recognition and coacervation of G-quadruplexes by a multifunctional disordered region in RECQ4 helicase
In this work, the authors report a three-step charge-driven coacervation model involving dynamic complexes between a positively charged IDR of human RECQ4 and G-quadruplexes. The IDR also interacts with Replication Protein A, implying RECQ4’s regulatory role.
- Anna C. Papageorgiou
- , Michaela Pospisilova
- & Konstantinos Tripsianes
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Intermolecular interactions underlie protein/peptide phase separation irrespective of sequence and structure at crowded milieu
In this work, the authors report that proteins/polypeptides with diverse sequences and structures can form liquid condensates, however with varying phase regimes and different modes of intermolecular interactions, spanning from electrostatic, hydrophobic and H-bond.
- Manisha Poudyal
- , Komal Patel
- & Samir K. Maji
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Defining the condensate landscape of fusion oncoproteins
Many fusion oncoproteins (FOs) form condensates, some form in the nucleus and regulate gene expression while others form in the cytoplasm and promote cell signaling. In this work, the authors report the analysis of physicochemical features to enable prediction of FO condensation behavior.
- Swarnendu Tripathi
- , Hazheen K. Shirnekhi
- & Richard W. Kriwacki
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Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions
Mixtures of prion-like low complexity domains (PLCDs) are found in condensates such as stress granules. In this work, the authors report how the interplay between homotypic and heterotypic interactions contributes to condensate formation by mixtures of PLCDs.
- Mina Farag
- , Wade M. Borcherds
- & Rohit V. Pappu
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Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology
Aberrant liquid-to-gel transition of biological condensates can lead to pathological fibrillization and disease. Here, the authors demonstrate that a small molecule, methylene blue, can decouple gelation from fibrillization of tau liquid droplets.
- Yongqi Huang
- , Jitao Wen
- & Meng Gao
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Visualizing single-molecule conformational transition and binding dynamics of intrinsically disordered proteins
Intrinsically disordered proteins (IDPs) are highly dynamic and play pivotal roles in cellular processes but can be difficult to study. Here, the authors develop a single-molecule nanocircuit for the real-time monitoring of c-Myc conformational transitions and their interaction with ligands.
- Wenzhe Liu
- , Limin Chen
- & Xuefeng Guo
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RNA-mediated demixing transition of low-density condensates
The cell interior is organized by diverse membrane-less condensates. Here, the authors reveal that the densities of certain condensates are surprisingly low, similar to the surrounding protoplasm and driven by cellular RNA as well as the crowded milieu.
- Taehyun Kim
- , Jaeyoon Yoo
- & Yongdae Shin
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Bombyx Vasa sequesters transposon mRNAs in nuage via phase separation requiring RNA binding and self-association
Bombyx Vasa assembles Vasa bodies, the site of transposon silencing by Siwi and Ago3-piRISC formation. Here, the authors show Vasa sequesters transposon mRNAs in Vasa bodies via phase separation requiring RNA binding and self-association of Vasa.
- Hiroya Yamazaki
- , Yurika Namba
- & Mikiko C. Siomi
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Inhibitor-3 inhibits Protein Phosphatase 1 via a metal binding dynamic protein–protein interaction
Protein phosphatase 1 (PP1) is regulated by intrinsically disordered proteins like inhibitor-3, I3. The authors show that I3 does not inhibit PP1 by forming a rigid complex but instead by binding dynamically with its active site metals, showing how flexibility is used in biology.
- Gautam Srivastava
- , Meng S. Choy
- & Wolfgang Peti
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Disease-relevant β2-microglobulin variants share a common amyloid fold
The authors use cryo-EM to determine amyloid fibrils structures of disease relevant variants of β2-microglobulin in vitro. Each variant is polymorphic, but all polymorphs from all samples are built from a a lego-like assembly of common building blocks, suggesting a one amyloid fold’ paradigm.
- Martin Wilkinson
- , Rodrigo U. Gallardo
- & Neil A. Ranson
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Barrier properties of Nup98 FG phases ruled by FG motif identity and inter-FG spacer length
The permeability barrier of the nuclear pore assembles from cohesive FG repeats. By systematic engineering and testing repeat variants, the authors pinpointed the sequence features that rule barrier assembly and transport selectivity.
- Sheung Chun Ng
- , Abin Biswas
- & Dirk Görlich
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Spatially non-uniform condensates emerge from dynamically arrested phase separation
Biomolecular condensates with internal structure allow cells to further organise their processes. In this work the authors investigate how condensates can obtain an internal structure with droplets of dilute phase inside via kinetic, rather than purely thermodynamic driving forces.
- Nadia A. Erkamp
- , Tomas Sneideris
- & Tuomas P. J. Knowles
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VGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid–liquid phase separation
Heart fibrosis involves a feedback loop where stiffening increases fibrosis-related gene expression in myofibroblasts. Here authors reveal the mechanosensitive nuclear translocation of VGLL3, where it phase separates and promotes collagen production, and show that its knock-out is protective after myocardial infarction.
- Yuma Horii
- , Shoichi Matsuda
- & Michio Nakaya
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Metamorphism in TDP-43 prion-like domain determines chaperone recognition
In this work, the authors show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease and stress the relevance of post-translationally modified chains as the targets for disease intervention.
- Jaime Carrasco
- , Rosa Antón
- & Javier Oroz
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Article
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PQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions
The nucleolus is a liquid-liquid phase separation droplet that dynamically changes under stress. Here, the authors report PQBP5/NOL10 is a critical component of the nucleolus, maintaining its structure and position in the nucleus during osmotic stress.
- Xiaocen Jin
- , Hikari Tanaka
- & Hitoshi Okazawa
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Biomolecular condensate phase diagrams with a combinatorial microdroplet platform
A central concept for characterising phase-separating systems is the phase diagram but generation of such diagrams for biomolecular systems is typically slow and low-throughput. Here the authors describe PhaseScan, a combinatorial droplet microfluidic platform for high-resolution acquisition of multidimensional biomolecular phase diagrams.
- William E. Arter
- , Runzhang Qi
- & Tuomas P. J. Knowles
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Detecting and quantifying liquid–liquid phase separation in living cells by model-free calibrated half-bleaching
It is currently debated how to reliably distinguish liquid–liquid phase separation (LLPS) from other mechanisms. Here the authors report model-free calibrated half-FRAP (MOCHA-FRAP) to probe the barrier at the condensate interface that is responsible for preferential internal mixing in LLPS.
- Fernando Muzzopappa
- , Johan Hummert
- & Fabian Erdel
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Hydrophobicity of arginine leads to reentrant liquid-liquid phase separation behaviors of arginine-rich proteins
Arginine-rich proteins display reentrant LLPS behavior with changes in salt and temperature due to the hydrophobicity of arginine. Controlling the reentrant LLPS behavior opens avenues for the bioengineering and drug delivery fields.
- Yuri Hong
- , Saeed Najafi
- & Dong Soo Hwang
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| Open Access
Phase separation modulates the assembly and dynamics of a polarity-related scaffold-signaling hub
The polarization of distinct scaffold-signaling hubs at opposite cell poles constitutes the basis of asymmetric cell division. Here, the authors show that phase separation serves as a general mechanism to regulate the assembly and dynamics of a new-pole scaffold-signaling hub.
- Wei Tan
- , Sihua Cheng
- & Wei Zhao
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Article
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A glutamine-based single α-helix scaffold to target globular proteins
Targeting biomedically relevant protein-protein interactions is a long-lasting challenge in medicinal chemistry. Here, the authors develop a single α-helical peptide scaffold that can be tailored to target globular proteins of biomedical interest.
- Albert Escobedo
- , Jonathan Piccirillo
- & Xavier Salvatella
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RG/RGG repeats in the C. elegans homologs of Nucleolin and GAR1 contribute to sub-nucleolar phase separation
Spaulding et al. survey RG/RGG repeats in C. elegans and identify the homologs of Nucleolin (NUCL-1) and GAR1 (GARR-1). RG/RGG repeats are dispensable for nucleolar accumulation but critical for sub-nucleolar phase separation.
- Emily L. Spaulding
- , Alexis M. Feidler
- & Dustin L. Updike
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| Open Access
Small molecules targeting the disordered transactivation domain of the androgen receptor induce the formation of collapsed helical states
In this work the authors report atomically detailed computer simulations revealing the binding mechanisms of small molecule drugs to an intrinsically disordered region of the androgen receptor, a castration-resistant prostate cancer drug target.
- Jiaqi Zhu
- , Xavier Salvatella
- & Paul Robustelli
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Article
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A simple thermodynamic description of phase separation of Nup98 FG domains
The nuclear pore complex (NPC) barrier is a selective phase assembled from disordered but cohesive FG domains. The authors provide a thermodynamic description of an FG phase that is ultimately simplified and yet closely recapitulates NPC transport selectivity.
- Sheung Chun Ng
- & Dirk Görlich
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Protein structural transitions critically transform the network connectivity and viscoelasticity of RNA-binding protein condensates but RNA can prevent it
In this work the authors propose a multiscale computational approach, integrating atomistic and coarse-grained models simulations, to study the thermodynamic and kinetic factors playing a major role in the liquid-to-solid transition of biomolecular condensates. It is revealed how the gradual accumulation of inter-protein β-sheets increases the viscosity of functional liquid-like condensates, transforming them into gel-like pathological aggregates, and it is also shown how high concentrations of RNA can decelerate such transition.
- Andres R. Tejedor
- , Ignacio Sanchez-Burgos
- & Jorge R. Espinosa
Biomolecular condensates form spatially inhomogeneous network fluids