A single N‐terminal phosphomimic disrupts TDP‐43 polymerization, phase separation, and RNA splicing

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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.

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Bibliographic citation: 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)

Creator: 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: 10.15252/embj.201797452

URN: urn:nbn:de:101:1-2022091006373791845823

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 15.08.2025, 7:29 AM CEST

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Associated

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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A single N‐terminal phosphomimic disrupts TDP‐43 polymerization, phase separation, and RNA splicing

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Other Objects (12)

The N-terminal dimerization is required for TDP-43 splicing activity

SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

Quantitative analysis of cryptic splicing associated with TDP-43 depletion

TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

ALS-linked TDP-43M337V knock-in mice exhibit splicing deregulation without neurodegeneration

TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition

RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis

C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress

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TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function

The N-terminal dimerization is required for TDP-43 splicing activity

SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

Quantitative analysis of cryptic splicing associated with TDP-43 depletion

TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

ALS-linked TDP-43M337V knock-in mice exhibit splicing deregulation without neurodegeneration

TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition

RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis

C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress

A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD

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Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function

The N-terminal dimerization is required for TDP-43 splicing activity

SUMOylation Regulates TDP-43 Splicing Activity and Nucleocytoplasmic Distribution

Quantitative analysis of cryptic splicing associated with TDP-43 depletion

TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD

ALS-linked TDP-43M337V knock-in mice exhibit splicing deregulation without neurodegeneration

TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition

RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy

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