Intrinsically disordered proteins articles within Nature Communications

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  • Article
    | Open Access

    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

  • Article
    | Open Access

    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

  • Article
    | Open Access

    “Intracellular phase separation is emerging as a universal principle for organizing biochemical reactions in time and space. Here the authors show that PopZ condensate dynamics support cell division and using PopZ modular architecture, the tunable PopTag platform was developed to enable designer condensates.”

    • Keren Lasker
    • , Steven Boeynaems
    •  & Lucy Shapiro

  • Article
    | Open Access

    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.

    • Derya Emin
    • , Yu P. Zhang
    •  & David Klenerman

  • Article
    | Open Access

    Amyotrophic Lateral Sclerosis related TDP-43 protein translocates to stress granules with a concomitant reduction in mobility. Here, the authors use single molecule tracking and find a stress-induced reduction in TDP-43 mobility also in the cytoplasm potentially relevant for TDP-43 aggregation.

    • Lisa Streit
    • , Timo Kuhn
    •  & Karin M. Danzer

  • Article
    | Open Access

    The authors of this work characterize the effect of amino acid substitution on α-synuclein (α-Syn) aggregation. Residues 38 and 42 (in addition to 39) within the P1 region of α-Syn affect amyloid formation. The effect of substitution at position 38 is dependent on the amino-acid introduced, suggesting that specific interactions control α -Syn aggregation.

    • Sabine M. Ulamec
    • , Roberto Maya-Martinez
    •  & David J. Brockwell

  • Article
    | Open Access

    SAP97/hDLG is a ubiquitous, alternatively spliced, and conserved modular scaffolding protein involved in the organization cell junctions and excitatory synapses. Here, authors confirm that SAP97/hDLG condenses in to nanosized molecular domains in both heterologous cells and hippocampal pyramidal neurons. Authors demonstrate that in vivo and in vitro condensation, molecular signatures of nanoscale condensates and exchange kinetics of SAP97/hDLG is modulated by the local availability of alternatively spliced isoforms. Additionally, SAP97/hDLG isoforms exhibits a differential sensitivity to Ca2+ bound Calmodulin, resulting in altered properties of nanocondensates and their real-time regulation

    • Premchand Rajeev
    • , Nivedita Singh
    •  & Deepak Nair

  • Article
    | Open Access

    Here the authors used single-molecule imaging and manipulation to study the mechanical effects of transcription factor Sox2 co-condensation with DNA and chromatin. They found that Sox2 condensates exert a high level of mechanical stress on DNA, but this stress is dramatically attenuated by nucleosomes assembled on the DNA.

    • Tuan Nguyen
    • , Sai Li
    •  & Shixin Liu

  • Article
    | Open Access

    How ATP-independent chaperones release their clients without energy input remains enigmatic. Here the authors discover that chaperone Spy uses its long, disordered N terminus to facilitate client release through competitive, dynamic intramolecular interactions with Spy’s client binding surface.

    • Wei He
    • , Xinming Li
    •  & Shu Quan

  • Article
    | Open Access

    The permeability barrier of nuclear pores is formed by disordered and yet self-interacting FG repeat domains, whose sequence heterogeneity is a challenge for mechanistic insights. Here the authors overcome this challenge and characterize the protein’s dynamics by applying NMR techniques to an FG phase system that has been simplified to its essentials.

    • Eszter E. Najbauer
    • , Sheung Chun Ng
    •  & Loren B. Andreas

  • Article
    | Open Access

    TCPTP is a non-receptor type protein tyrosine phosphatase involved in various signalling pathways. Here, the authors provide structural insights into TCPTP activation, showing that TCPTP is inhibited by its C-terminal tail, which can be displaced by the cytosolic tail of integrin-α1, leading to activation.

    • Jai Prakash Singh
    • , Yang Li
    •  & Tzu-Ching Meng

  • Article
    | Open Access

    Many interactions between viral and host proteins are mediated by short peptide motifs. Here, using a phage-based viral peptide library, the authors identify 269 peptide-based interactions for 18 coronaviruses, including an interaction between SARS-CoV-2 N and G3BP1/2 that affects stress granules.

    • Thomas Kruse
    • , Caroline Benz
    •  & Ylva Ivarsson

  • Article
    | Open Access

    G51D mutation of α-synuclein (α-syn) causes a subset of familial Parkinson’s disease that is characterized by an early onset and rapid progression of the disease. Here, the authors present the cryo-EM structure of full-length G51D α-syn fibrils that is distinct from other known α-syn fibril structures, and they show that G51D fibrils can cross-seed wild-type (WT) α-syn and that these cross-seeded WT fibrils replicate the G51D fibril structure.

    • Yunpeng Sun
    • , Houfang Long
    •  & Cong Liu

  • Article
    | Open Access

    Phase-separated biomolecular condensates are implicated in a myriad of biological processes. Here the authors apply optical tweezers to characterize the viscoelasticity and interfacial tension of a range of condensates, finding that condensates can deviate from simple fluids in opposite directions; and identify shear relaxation as a governing measure of condensate dynamics.

    • Archishman Ghosh
    • , Divya Kota
    •  & Huan-Xiang Zhou

  • Article
    | Open Access

    Phase separation has been suggested as a mechanism for heterochromatin formation through condensation of heterochromatin-associated factors. Here the authors show Polycomb complex PRC1 forms condensates on chromatin. Using optogenetic tools they nucleate local Polycomb condensates to show that this phase separation leads to subsequent histone modifications and chromatin compaction.

    • Jorine M. Eeftens
    • , Manya Kapoor
    •  & Clifford P. Brangwynne

  • Article
    | Open Access

    Protein binding by the Hsp70/J-domain protein (JDP) chaperones prevents aggregation of the client protein. Here, the authors show that DnaJC7 binds preferentially to natively folded wild-type tau, via a β-turn element in tau that contains the known amyloid motif, while aggregation-prone tau mutants are recognized with reduced affinity.

    • Zhiqiang Hou
    • , Pawel M. Wydorski
    •  & Lukasz A. Joachimiak

  • Article
    | Open Access

    Nuclear import receptors (NIRs) regulate self-association of RNA-binding proteins as phase modifiers, while C9orf72-derived arginine-rich polydipeptides lead to aberrant phase transitions. Here the authors show in molecular basis how arginine-rich poly-dipeptides impede the ability of NIRs, particularly Kapβ2.

    • Hitoki Nanaura
    • , Honoka Kawamukai
    •  & Eiichiro Mori

  • Article
    | Open Access

    The intrinsic disorder of histone tails poses challenges in their characterization. Here the authors apply extensive molecular dynamics simulations of the full nucleosome to show reversible binding to DNA with specific binding modes of different types of histone tails, where charge-altering modifications suppress tail-DNA interactions and may boost interactions between nucleosomes and nucleosome-binding proteins.

    • Yunhui Peng
    • , Shuxiang Li
    •  & Anna R. Panchenko

  • Article
    | Open Access

    The nucleation mechanisms of biological protein phase separation are poorly understood. Here, the authors perform time-resolved SAXS experiments with the low-complexity domain (LCD) of hnRNPA1 and uncover multiple kinetic regimes on the micro- to millisecond timescale. Initially, individual proteins collapse. Nucleation then occurs via two steps distinguished by their protein cluster size distributions.

    • Erik W. Martin
    • , Tyler S. Harmon
    •  & Tanja Mittag

  • Article
    | Open Access

    Huntingtin exon-1 (HTTex1) consists of a N-terminal N17 domain, the disease causing polyQ domain and a C-terminal proline-rich domain (PRD). Here, the authors combine electron paramagnetic resonance (EPR), solid-state NMR with other biophysical method to characterise the structural differences of various HTTex1 fibril types with different toxicity and find that the dynamics and entanglement of the PRD domain differs among them and that the HTTex1 fibrils can be interconverted.

    • J. Mario Isas
    • , Nitin K. Pandey
    •  & Ansgar B. Siemer

  • Article
    | Open Access

    Emerging evidence suggests that exit from pluripotency is a regulated, rather than passive process. Here the authors identify a requirement for SS18-mediated Brg/Brahma-associated factors (BAF) chromatin remodeling complex assembly during exit from pluripotency, and that SS18 promotes BAF assembly through liquidliquid phase separation.

    • Junqi Kuang
    • , Ziwei Zhai
    •  & Duanqing Pei

  • Article
    | Open Access

    The permeability barrier of nuclear pore complexes blocks passage of inert macromolecules but allows rapid, receptor-mediated, and RanGTPase-driven transport of cargoes up to ribosome size. The authors now show that such a barrier can be faithfully recapitulated by an ultimately simplified FG phase assembled solely from a tandemly repeated 12mer GLFG peptide.

    • Sheung Chun Ng
    • , Thomas Güttler
    •  & Dirk Görlich

  • Article
    | Open Access

    Amyloid aggregation of mutant p53 contributes to its loss of tumor suppressor function and oncogenic gain-of-function. Here, the authors use a protein mimetic to abrogate mutant p53 aggregation and rescue p53 function, which inhibits cancer cell proliferation in vitro and halts tumor growth in vivo.

    • L. Palanikumar
    • , Laura Karpauskaite
    •  & Mazin Magzoub

  • Article
    | Open Access

    The intrinsically disordered acidic activation domain (AD) of the yeast transcription factor Gal4 acts through binding to the Med15 subunit of the Mediator complex. Here, the authors show that Gal4 interacts with Med15 through an identical fuzzy binding mechanism as Gcn4 AD, which has a different sequence, revealing a common sequence-independent mechanism for AD-Mediator binding. In contrast, Gal4 AD binds to the Gal80 repressor as a structured polypeptide, which strongly suggests that the structured binding partner dictates the type of protein–protein interaction for an intrinsically disordered protein.

    • Lisa M. Tuttle
    • , Derek Pacheco
    •  & Rachel E. Klevit

  • Article
    | Open Access

    Intrinsically disordered FG-Nups line the Nuclear Pore Complex (NPC) lumen and form a selective barrier where transport of most proteins is inhibited, whereas specific transporter proteins are able to pass. Here, the authors reconstitute the selective behaviour of the NPC by introducing a rationally designed artificial FG-Nup that demonstrates that no specific spacer sequence nor a spatial segregation of different FG-motif types are needed to create selective NPCs.

    • Alessio Fragasso
    • , Hendrik W. de Vries
    •  & Cees Dekker

  • Article
    | Open Access

    Here, the authors present DisCo (Disassembly of Condensates), a method that allows the fast, inducible, and specific disruption of tagged condensates in mammalian cells. DisCo uses chemical dimerizers to induce the recruitment of a ligand into condensates leading to condensate disassembly.

    • Carmen N. Hernández-Candia
    • , Sarah Pearce
    •  & Chandra L. Tucker

  • Article
    | Open Access

    It is currently challenging to identify protein structures at low concentrations. Here the authors report optical tweezers-coupled Raman spectroscopy to generate tunable and reproducible SERS enhancements with single-molecule level sensitivity and use the method to detect protein structural features.

    • Xin Dai
    • , Wenhao Fu
    •  & Jinqing Huang

  • Article
    | Open Access

    Elucidating the molecular driving forces underlying liquid–liquid phase separation is a key objective for understanding biological function and malfunction. Here the authors show that a wide range of cellular proteins, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, which form condensates at low salt concentrations, can reenter a phase-separated regime at high salt concentrations.

    • Georg Krainer
    • , Timothy J. Welsh
    •  & Tuomas P. J. Knowles

  • Article
    | Open Access

    Epigallocatechin gallate (EGCG) is a catechin flavonoid which induces apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Here authors use an interdisciplinary approach to show a direct interaction between EGCG and the tumor suppressor p53 and demonstrate that EGCG inhibits ubiquitination of p53 by MDM2.

    • Jing Zhao
    • , Alan Blayney
    •  & Chunyu Wang

  • Article
    | Open Access

    Mapping free energy landscapes of complex multi-funneled metamorphic proteins and weakly-funneled intrinsically disordered proteins (IDPs) remains challenging. Here authors present a parallel-tempering method that takes advantage of accelerated water dynamics for efficient and accurate conformational sampling across a wide variety of proteins.

    • Rajeswari Appadurai
    • , Jayashree Nagesh
    •  & Anand Srivastava

  • Article
    | Open Access

    Liquid ribonucleoprotein condensates typically involve a dense network of multiple proteins and RNAs. Here, the authors employ a minimal system composed of Prion-like polypeptides (PLP), Arg-rich polypeptides (RRP), and RNA to form biphasic condensates with diverse morphologies tunable via mixture stoichiometry and hierarchy of intermolecular interactions.

    • Taranpreet Kaur
    • , Muralikrishna Raju
    •  & Priya R. Banerjee

  • Article
    | Open Access

    Synaptic vesicle clusters were proposed to represent phase separated condensates. Here, the authors show that only two proteins, synapsin and synaptophysin, are sufficient to make vesicle clusters in fibroblasts which are similar to those found at synapses in morphology and liquid-like properties.

    • Daehun Park
    • , Yumei Wu
    •  & Sunghoe Chang

  • Article
    | Open Access

    Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) shuttles between the nucleus and cytoplasm to regulate gene expression and RNA metabolism and its low complexity (LC) C-terminal domain facilitates liquid–liquid phase separation and amyloid aggregation. Here, the authors present the cryo-EM structure of amyloid fibrils formed by the hnRNPA1 LC domain, which reveals that the hnRNPA1 nuclear localization sequence forms the fibril core, and they discuss how ALS-causing mutations affect fibril stability.

    • Yunpeng Sun
    • , Kun Zhao
    •  & Dan Li

  • Article
    | Open Access

    Cyclophilin A (CypA) is a peptidylprolyl isomerase that also has chaperone activity and interacts with the intrinsically disordered protein α-Synuclein (aSyn). Here, the authors combine NMR measurements and biochemical experiments to characterise the interplay between the catalysis of proline isomerization and molecular chaperone activity of CypA and find that both activities have opposing effects on aSyn and further show that the that cis/trans isomerization outpowers the holding activity of CypA.

    • Filippo Favretto
    • , David Flores
    •  & Markus Zweckstetter

  • Article
    | Open Access

    The SARS-CoV-2 viral genome is encapsulated by the nucleocapsid protein (NSARS-CoV-2) that is essential for viral replication. Here, the authors show that RNA induces liquid-liquid phase separation of NSARS-CoV-2 and how NSARS-CoV-2 phosphorylation modulates RNA-binding and phase separation and that these RNA/NSARS-CoV-2-droplets recruit and concentrate the SARS-CoV-2 RNA-dependent RNA polymerase complex in vitro, which would enable high initiation and elongation rates during viral transcription.

    • Adriana Savastano
    • , Alain Ibáñez de Opakua
    •  & Markus Zweckstetter

  • Article
    | Open Access

    The design principles underlying biomolecular phase separation of membrane-less organelles remain poorly understood. Using model homopolymers, Fisher et al. show that the formation kinetics of coexisting liquid phases can be tuned by exploiting differences between arginine and lysine residues.

    • Rachel S. Fisher
    •  & Shana Elbaum-Garfinkle

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