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Arginine-enriched mixed-charge domains provide cohesion for nuclear speckle condensation

Jamie A. Greig, Tu Anh Nguyen, Michelle Lee, Alex S. Holehouse, Ammon E. Posey, Rohit V. Pappu, Gregory Jedd
doi: https://doi.org/10.1101/771592
Jamie A. Greig
1Temasek Life Sciences Laboratory & Department of Biological Sciences, The National University of Singapore, Singapore 117604
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Tu Anh Nguyen
1Temasek Life Sciences Laboratory & Department of Biological Sciences, The National University of Singapore, Singapore 117604
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Michelle Lee
1Temasek Life Sciences Laboratory & Department of Biological Sciences, The National University of Singapore, Singapore 117604
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Alex S. Holehouse
2Department of Biomedical Engineering and Center for Science & Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, MO 63130, USA
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Ammon E. Posey
2Department of Biomedical Engineering and Center for Science & Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, MO 63130, USA
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Rohit V. Pappu
2Department of Biomedical Engineering and Center for Science & Engineering of Living Systems (CSELS), Washington University in St. Louis, St. Louis, MO 63130, USA
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Gregory Jedd
1Temasek Life Sciences Laboratory & Department of Biological Sciences, The National University of Singapore, Singapore 117604
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  • For correspondence: gregory@tll.org.sg
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Abstract

Low-complexity protein domains promote the formation of various biomolecular condensates. However, in many cases, the precise sequence features governing condensate formation and identity remain unclear. Here, we investigate the role of intrinsically disordered mixed-charge domains (MCDs) in nuclear speckle condensation. Proteins composed exclusively of arginine/aspartic-acid dipeptide repeats undergo length-dependent condensation and speckle incorporation. Substituting arginine with lysine in synthetic and natural speckle-associated MCDs abolishes these activities, identifying a key role for multivalent contacts through arginine’s guanidinium ion. MCDs can synergise with a speckle-associated RNA recognition motif to promote speckle specificity and residence. MCD behaviour is tuneable through net-charge: increasing negative charge abolishes condensation and speckle incorporation. By contrast, increasing positive charge through arginine leads to enhanced condensation, speckle enlargement, decreased splicing factor mobility, and defective mRNA export. Together, these results identify key sequence determinants of MCD-promoted speckle condensation, and link the speckle’s dynamic material properties with function in mRNA processing.

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Posted September 16, 2019.
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Arginine-enriched mixed-charge domains provide cohesion for nuclear speckle condensation
Jamie A. Greig, Tu Anh Nguyen, Michelle Lee, Alex S. Holehouse, Ammon E. Posey, Rohit V. Pappu, Gregory Jedd
bioRxiv 771592; doi: https://doi.org/10.1101/771592
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Arginine-enriched mixed-charge domains provide cohesion for nuclear speckle condensation
Jamie A. Greig, Tu Anh Nguyen, Michelle Lee, Alex S. Holehouse, Ammon E. Posey, Rohit V. Pappu, Gregory Jedd
bioRxiv 771592; doi: https://doi.org/10.1101/771592

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