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  • 1
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    A composition-dependent molecular clutch between T cell signaling condensates and actin (2019)
    eLife Sciences Publications
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    Publication Date: 2022-05-26
    Description: © 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.
    Description: 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
    Description: 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
    Type: Article
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  • 2
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    A composition-dependent molecular clutch between T cell signaling condensates and actin (2019)
    eLife Sciences Publications
    Details
    Publication Date: 2019-07-03
    Description: 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.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
    Published by eLife Sciences Publications
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  • 3
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    A quantitative inventory of yeast P body proteins reveals principles of composition and specificity (2020)
    eLife Sciences Publications
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    Publication Date: 2020-06-19
    Description: 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.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
    Published by eLife Sciences Publications
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  • 4
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    Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites (2017)
    eLife Sciences Publications
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    Publication Date: 2017-09-26
    Description: 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.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
    Published by eLife Sciences Publications
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  • 5
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    Three-color single molecule imaging shows WASP detachment from Arp2/3 complex triggers actin filament branch formation (2013)
    eLife Sciences Publications
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    Publication Date: 2013-09-03
    Description: 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.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
    Published by eLife Sciences Publications
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  • 6
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    Intrinsically disordered linkers determine the interplay between phase separation and gelation in multivalent proteins (2017)
    eLife Sciences Publications
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    Publication Date: 2017-11-01
    Description: 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.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
    Published by eLife Sciences Publications
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  • 7
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    Phase transitions of multivalent proteins can promote clustering of membrane receptors (2014)
    eLife Sciences Publications
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    Publication Date: 2014-10-16
    Description: 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.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
    Published by eLife Sciences Publications
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  • 8
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    Actin is an evolutionarily-conserved damage-associated molecular pattern that signals tissue injury in Drosophila melanogaster (2016)
    eLife Sciences Publications
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    Publication Date: 2016-11-22
    Description: 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.
    Electronic ISSN: 2050-084X
    Topics: Biology , Medicine , Natural Sciences in General
    Published by eLife Sciences Publications
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  • 9
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    Was There a Pliocene-Pleistocene Fluvial-Lacustrine Connection between Death Valley and the Colorado River? (1995)
    Cambridge University Press
    Details
    Publication Date: 1995-05-01
    Description: Since the turn of the century, a Pliocene-Pleistocene connection between the Death Valley-Owens River pluvial system and the Colorado River drainage basin has been frequently postulated. The two most commonly proposed routes involve (1) a southward overflow from the Death Valley Lake system or (2) southward migration of the Mojave River between its present course and a more southerly route. Under the present topographic regime, a Death Valley Lake capable of overflowing the bedrock saddle at Ludlow, California and discharging southward into the Bristol, Cadiz, and Danby Lake basins (and eventually the Colorado River) would be over 12,000 km2 in size. Few surface and subsurface indicators exist to support either a fluvial or lacustrine connection. Evidence from deep cores and boreholes drilled in Soda, Bristol, Cadiz, and Danby dry lake basins indicate that a hydrologic connection has not occurred during the past 4 myr. No well-documented paleoshoreline features have been located at elevations corresponding to the above hydrologic systems in Death Valley, Silver-Soda, Bristol, or Danby Lake basins. In the Cadiz, Silurian, and Broadwell basins these features have not been found at all. Therefore, we conclude that a hydrologic connection between the Death Valley-Owens River system and the Colorado River has not occurred along either of these routes since the middle Pliocene.
    Print ISSN: 0033-5894
    Electronic ISSN: 1096-0287
    Topics: Geography , Geosciences
    Published by Cambridge University Press
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