A single N‐terminal phosphomimic disrupts TDP‐43 polymerization, phase separation, and RNA splicing
Abstract: TDP‐43 is an RNA‐binding protein active in splicing that concentrates into membraneless ribonucleoprotein granules and forms aggregates in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Although best known for its predominantly disordered C‐terminal domain which mediates ALS inclusions, TDP‐43 has a globular N‐terminal domain (NTD). Here, we show that TDP‐43 NTD assembles into head‐to‐tail linear chains and that phosphomimetic substitution at S48 disrupts TDP‐43 polymeric assembly, discourages liquid–liquid phase separation (LLPS) in vitro, fluidizes liquid–liquid phase separated nuclear TDP‐43 reporter constructs in cells, and disrupts RNA splicing activity. Finally, we present the solution NMR structure of a head‐to‐tail NTD dimer comprised of two engineered variants that allow saturation of the native polymerization interface while disrupting higher‐order polymerization. These data provide structural detail for the established mechanistic role of the well‐folded TDP‐43 NTD in splicing and link this function to LLPS. In addition, the fusion‐tag solubilized, recombinant form of TDP‐43 full‐length protein developed here will enable future phase separation and in vitro biochemical assays on TDP‐43 function and interactions that have been hampered in the past by TDP‐43 aggregation.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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A single N‐terminal phosphomimic disrupts TDP‐43 polymerization, phase separation, and RNA splicing ; volume:37 ; number:5 ; year:2018 ; extent:18
The EMBO journal / European Molecular Biology Organization ; 37, Heft 5 (2018) (gesamt 18)
- Urheber
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Wang, Ailin
Conicella, Alexander E.
Schmidt, Hermann Broder
Martin, Erik W.
Rhoads, Shannon N.
Reeb, Ashley N.
Nourse, Amanda
Ramirez Montero, Daniel
Ryan, Veronica H.
Rohatgi, Rajat
Shewmaker, Frank
Naik, Mandar T.
Mittag, Tanja
Ayala, Yuna M.
Fawzi, Nicolas L.
- DOI
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10.15252/embj.201797452
- URN
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urn:nbn:de:101:1-2022091006373791845823
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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15.08.2025, 07:29 MESZ
Datenpartner
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Beteiligte
- Wang, Ailin
- Conicella, Alexander E.
- Schmidt, Hermann Broder
- Martin, Erik W.
- Rhoads, Shannon N.
- Reeb, Ashley N.
- Nourse, Amanda
- Ramirez Montero, Daniel
- Ryan, Veronica H.
- Rohatgi, Rajat
- Shewmaker, Frank
- Naik, Mandar T.
- Mittag, Tanja
- Ayala, Yuna M.
- Fawzi, Nicolas L.
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