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  • 1
    Publikationsdatum: 2022-05-26
    Beschreibung: © The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Ditlev, J. A., Vega, A. R., Köster, D. V., Su, X., Tani, T., Lakoduk, A. M., Vale, R. D., Mayor, S., Jaqaman, K., & Rosen, M. K. A composition-dependent molecular clutch between T cell signaling condensates and actin. Elife, 8, (2019): e42695, doi:10.7554/eLife.42695.
    Beschreibung: During T cell activation, biomolecular condensates form at the immunological synapse (IS) through multivalency-driven phase separation of LAT, Grb2, Sos1, SLP-76, Nck, and WASP. These condensates move radially at the IS, traversing successive radially-oriented and concentric actin networks. To understand this movement, we biochemically reconstituted LAT condensates with actomyosin filaments. We found that basic regions of Nck and N-WASP/WASP promote association and co-movement of LAT condensates with actin, indicating conversion of weak individual affinities to high collective affinity upon phase separation. Condensates lacking these components were propelled differently, without strong actin adhesion. In cells, LAT condensates lost Nck as radial actin transitioned to the concentric network, and engineered condensates constitutively binding actin moved aberrantly. Our data show that Nck and WASP form a clutch between LAT condensates and actin in vitro and suggest that compositional changes may enable condensate movement by distinct actin networks in different regions of the IS. https://doi.org/10.7554/eLife.42695.001
    Beschreibung: We thank L Rice, J Hammer III, and our fellow HCIA Summer Institute scientists for stimulating discussions about this study. This work was supported by a Howard Hughes Medical Institute Collaborative Innovation Award, the Welch Foundation (I-1544 to MKR), a JC Bose Fellowship from the Department of Science and Technology, government of India (SM), a Margadarshi Fellowship from the Wellcome Trust – Department of Biotechnology, India Alliance (IA/M/15/1/502018 to SM), NIH (R01 GM100160 to TT) (R35 GM119619 to KJ), a CPRIT Recruitment Award (R1216 to KJ), and the UT Southwestern Endowed Scholars Program (KJ). Research in the Rosen lab is supported by the Howard Hughes Medical Institute. JAD was supported by a National Research Service Award F32 (F32 DK101188). ARV was supported by a CPRIT Training Grant (RP140110, PI: Michael White). DVK was supported by fellowships of the AXA Research Fund and the National Centre for Biological Sciences, Tata Institute for Fundamental Research. XS was supported by a Cancer Research Institute Irvington postdoctoral fellowship.
    Repository-Name: Woods Hole Open Access Server
    Materialart: Article
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
    Publikationsdatum: 2019-07-03
    Beschreibung: During T cell activation, biomolecular condensates form at the immunological synapse (IS) through multivalency-driven phase separation of LAT, Grb2, Sos1, SLP-76, Nck, and WASP. These condensates move radially at the IS, traversing successive radially-oriented and concentric actin networks. To understand this movement, we biochemically reconstituted LAT condensates with actomyosin filaments. We found that basic regions of Nck and N-WASP/WASP promote association and co-movement of LAT condensates with actin, indicating conversion of weak individual affinities to high collective affinity upon phase separation. Condensates lacking these components were propelled differently, without strong actin adhesion. In cells, LAT condensates lost Nck as radial actin transitioned to the concentric network, and engineered condensates constitutively binding actin moved aberrantly. Our data show that Nck and WASP form a clutch between LAT condensates and actin in vitro and suggest that compositional changes may enable condensate movement by distinct actin networks in different regions of the IS.
    Digitale ISSN: 2050-084X
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Standort Signatur Erwartet Verfügbarkeit
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  • 3
    Publikationsdatum: 2020-06-19
    Beschreibung: P bodies are archetypal biomolecular condensates that concentrate proteins and RNA without a surrounding membrane. While dozens of P body proteins are known, the concentrations of components in the compartment have not been measured. We used live cell imaging to generate a quantitative inventory of the major proteins in yeast P bodies. Only seven proteins are highly concentrated in P bodies (5.1–15µM); the 24 others examined are appreciably lower (most ≤ 2.6µM). P body concentration correlates inversely with cytoplasmic exchange rate. Sequence elements driving Dcp2 concentration into P bodies are distributed across the protein and act synergistically. Our data indicate that P bodies, and probably other condensates, are compositionally simpler than suggested by proteomic analyses, with implications for specificity, reconstitution and evolution.
    Digitale ISSN: 2050-084X
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Standort Signatur Erwartet Verfügbarkeit
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  • 4
    Publikationsdatum: 2017-09-26
    Beschreibung: The Rho GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization, which underpins diverse cellular processes. Here we report the structure of a WRC-Rac1 complex determined by cryo-electron microscopy. Surprisingly, Rac1 is not located at the binding site on the Sra1 subunit of the WRC previously identified by mutagenesis and biochemical data. Rather, it binds to a distinct, conserved site on the opposite end of Sra1. Biophysical and biochemical data on WRC mutants confirm that Rac1 binds to both sites, with the newly identified site having higher affinity and both sites required for WRC activation. Our data reveal that the WRC is activated by simultaneous engagement of two Rac1 molecules, suggesting a mechanism by which cells may sense the density of active Rac1 at membranes to precisely control actin assembly.
    Digitale ISSN: 2050-084X
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Standort Signatur Erwartet Verfügbarkeit
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  • 5
    Publikationsdatum: 2013-09-03
    Beschreibung: During cell locomotion and endocytosis, membrane-tethered WASP proteins stimulate actin filament nucleation by the Arp2/3 complex. This process generates highly branched arrays of filaments that grow toward the membrane to which they are tethered, a conflict that seemingly would restrict filament growth. Using three-color single-molecule imaging in vitro we revealed how the dynamic associations of Arp2/3 complex with mother filament and WASP are temporally coordinated with initiation of daughter filament growth. We found that WASP proteins dissociated from filament-bound Arp2/3 complex prior to new filament growth. Further, mutations that accelerated release of WASP from filament-bound Arp2/3 complex proportionally accelerated branch formation. These data suggest that while WASP promotes formation of pre-nucleation complexes, filament growth cannot occur until it is triggered by WASP release. This provides a mechanism by which membrane-bound WASP proteins can stimulate network growth without restraining it.
    Digitale ISSN: 2050-084X
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Standort Signatur Erwartet Verfügbarkeit
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  • 6
    Publikationsdatum: 2017-11-01
    Beschreibung: Phase transitions of linear multivalent proteins control the reversible formation of many intracellular membraneless bodies. Specific non-covalent crosslinks involving domains/motifs lead to system-spanning networks referred to as gels. Gelation transitions can occur with or without phase separation. In gelation driven by phase separation multivalent proteins and their ligands condense into dense droplets, and gels form within droplets. System spanning networks can also form without a condensation or demixing of proteins into droplets. Gelation driven by phase separation requires lower protein concentrations, and seems to be the biologically preferred mechanism for forming membraneless bodies. Here, we use coarse-grained computer simulations and the theory of associative polymers to uncover the physical properties of intrinsically disordered linkers that determine the extent to which gelation of linear multivalent proteins is driven by phase separation. Our findings are relevant for understanding how sequence-encoded information in disordered linkers influences phase transitions of multivalent proteins.
    Digitale ISSN: 2050-084X
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Standort Signatur Erwartet Verfügbarkeit
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  • 7
    Publikationsdatum: 2014-10-16
    Beschreibung: Clustering of proteins into micrometer-sized structures at membranes is observed in many signaling pathways. Most models of clustering are specific to particular systems, and relationships between physical properties of the clusters and their molecular components are not well understood. We report biochemical reconstitution on supported lipid bilayers of protein clusters containing the adhesion receptor Nephrin and its cytoplasmic partners, Nck and N-WASP. With Nephrin attached to the bilayer, multivalent interactions enable these proteins to polymerize on the membrane surface and undergo two-dimensional phase separation, producing micrometer-sized clusters. Dynamics and thermodynamics of the clusters are modulated by the valencies and affinities of the interacting species. In the presence of the Arp2/3 complex, the clusters assemble actin filaments, suggesting that clustering of regulatory factors could promote local actin assembly at membranes. Interactions between multivalent proteins could be a general mechanism for cytoplasmic adaptor proteins to organize membrane receptors into micrometer-scale signaling zones.
    Digitale ISSN: 2050-084X
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Standort Signatur Erwartet Verfügbarkeit
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  • 8
    Publikationsdatum: 2016-11-22
    Beschreibung: Damage-associated molecular patterns (DAMPs) are molecules released by dead cells that trigger sterile inflammation and, in vertebrates, adaptive immunity. Actin is a DAMP detected in mammals by the receptor, DNGR-1, expressed by dendritic cells (DCs). DNGR-1 is phosphorylated by Src-family kinases and recruits the tyrosine kinase Syk to promote DC cross-presentation of dead cell-associated antigens. Here we report that actin is also a DAMP in invertebrates that lack DCs and adaptive immunity. Administration of actin to Drosophila melanogaster triggers a response characterised by selective induction of STAT target genes in the fat body through the cytokine Upd3 and its JAK/STAT-coupled receptor, Domeless. Notably, this response requires signalling via Shark, the Drosophila orthologue of Syk, and Src42A, a Drosophila Src-family kinase, and is dependent on Nox activity. Thus, extracellular actin detection via a Src-family kinase-dependent cascade is an ancient means of detecting cell injury that precedes the evolution of adaptive immunity.
    Digitale ISSN: 2050-084X
    Thema: Biologie , Medizin , Allgemeine Naturwissenschaft
    Standort Signatur Erwartet Verfügbarkeit
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