ArticleProtein science : a publication of the Protein Society2024
A complex network of interdomain interactions underlies the conformational ensemble of monomeric TDP-43 and modulates its phase behavior.
Article in Protein science : a publication of the Protein Society, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 40 citations in OpenAlex.
- Unraveling in vitro phase separation and aggregation properties of the structured region of FMRP and the impact of Fragile X syndrome-linked mutations.The FEBS journal · 2026Article
- TDP-43 controls RNA structure through high affinity lattice interactions.Nature communications · 2026Article
- Paraspeckle condensation is controlled via TDP-43 polymerization and linked to neuroprotection.Nature cell biology · 2026Article
- Liquid-Liquid Phase Separation in Major Hallmarks of Cancer.Cell proliferation · 2026Review
- Multiscale simulations of folded and intrinsically disordered region-containing protein condensates.Biophysical journal · 2026Article
- TDP-43 controls RNA structure through high affinity lattice interactions.bioRxiv : the preprint server for biology · 2025Article
- Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain.Nature communications · 2025Article
- Optimized protein-water interactions and torsional refinements yield balanced atomistic protein force fields.Nature communications · 2025Article
- Differential conformational expansion of NUP98-HOXA9 oncoprotein from nanosized assemblies to macrophases.Nature communications · 2025Article
- Elucidation of the Molecular Interaction Network Underlying Full-Length FUS Conformational Transitions and Its Phase Separation Using Atomistic Simulations.The journal of physical chemistry. B · 2025Article
- Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.Cell · 2025Article
- Expanding the molecular grammar of polar residues and arginine in FUS phase separation.Nature chemical biology · 2025Article
- Transient Interdomain Interactions Modulate the Monomeric Structural Ensemble and Self-Assembly of Huntingtin Exon 1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- A disordered linker in the Polycomb protein Polyhomeotic tunes phase separation and oligomerization.Molecular cell · 2025Article
- Molecular simulations of enzymatic phosphorylation of disordered proteins and their condensates.Nature communications · 2025Article
- The Regulation of TDP-43 Structure and Phase Transitions: A Review.The protein journal · 2025Review
- RNA binding tunes the conformational plasticity and intradomain stability of TDP-43 tandem RNA recognition motifs.Biophysical journal · 2024Article
- Structural and Functional Relevance of Charge Based Transient Interactions inside Intrinsically Disordered Proteins.bioRxiv : the preprint server for biology · 2024Article
- Weighted families of contact maps to characterize conformational ensembles of (highly-)flexible proteins.Bioinformatics (Oxford, England) · 2024Article
- Fundamental Aspects of Phase-Separated Biomolecular Condensates.Chemical reviews · 2024Review
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
TAR DNA-binding protein 43 (TDP-43) is a multidomain protein involved in the regulation of RNA metabolism, and its aggregates have been observed in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Numerous studies indicate TDP-43 can undergo liquid-liquid phase separation (LLPS) in vitro and is a component of biological condensates. Homo-oligomerization via the folded N-terminal domain (aa:1-77) and the conserved helical region (aa:319-341) of the disordered, C-terminal domain is found to be an important driver of TDP-43 phase separation. However, a comprehensive molecular view of TDP-43 phase separation, particularly regarding the nature of heterodomain interactions, is lacking due to the challenges associated with its stability and purification. Here, we utilize all-atom and coarse-grained (CG) molecular dynamics (MD) simulations to uncover the network of interdomain interactions implicated in TDP-43 phase separation. All-atom simulations uncovered the presence of transient, interdomain interactions involving flexible linkers, RNA-recognition motif (RRM) domains and a charged segment of disordered C-terminal domain (CTD). CG simulations indicate these inter-domain interactions which affect the conformational landscape of TDP-43 in the dilute phase are also prevalent in the condensed phase. Finally, sequence and surface charge distribution analysis coupled with all-atom simulations (at high salt) confirmed that the transient interdomain contacts are predominantly electrostatic in nature. Overall, our findings from multiscale simulations lead to a greater appreciation of the complex interaction network underlying the structural landscape and phase separation of TDP-43.
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