Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain

Pathological inclusions of the C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43) are neurodegenerative hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, yet CTD's aggregation propensity complicates structural characterization of native TDP-43. Here we propose structural models for the physiological multimerization of TDP-43 CTD's conserved region (CR) essential for TDP-43 RNA processing. Using NMR spectroscopy, we establish that the native state of TDP-43 CR at physiological conditions is α-helical. Hydrophobic residues drive CR helix-helix assembly, phase separation, and TDP-43 nuclear retention, while polar residues down regulate these processes. An integrative approach combining analytical ultracentrifugation, NMR-derived contacts, AlphaFold2-Multimer modeling, and all-atom molecular dynamics simulations together suggest that TDP-43 CR forms dynamic, multimeric helical assemblies stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. These structures show how ALS-associated mutations disrupt TDP-43 function and provide pharmacologically targetable structures to prevent its conversion into pathogenic β-sheet aggregates.

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Publication Details

Journal
Nature Communications
Published
2025-11-26
DOI
https://doi.org/10.1038/s41467-025-65546-w
Citations
5
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
6.95

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article

Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain

Yuna M. Ayala, Priyesh Mohanty, Lohany D. Mamede, Renjith Viswanathan et al.
5 citations
Nature Communications
Amyotrophic Lateral Sclerosis Research
6.95
article

Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain

Yuna M. Ayala, Priyesh Mohanty, Lohany D. Mamede, Renjith Viswanathan, Azamat Rizuan, Szu‐Huan Wang, José F. Mercado Ortiz, Victoria Johnson, Rodolfo Ghirlando, Nicolas Lux Fawzi, Jeetain Mittal, Patricia M. dos Passos, Leanna Bai, Jayakrishna Shenoy, Amanda R. Titus, Julia Zaborowksy
article en
5 citations

Abstract

Pathological inclusions of the C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43) are neurodegenerative hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, yet CTD's aggregation propensity complicates structural characterization of native TDP-43. Here we propose structural models for the physiological multimerization of TDP-43 CTD's conserved region (CR) essential for TDP-43 RNA processing. Using NMR spectroscopy, we establish that the native state of TDP-43 CR at physiological conditions is α-helical. Hydrophobic residues drive CR helix-helix assembly, phase separation, and TDP-43 nuclear retention, while polar residues down regulate these processes. An integrative approach combining analytical ultracentrifugation, NMR-derived contacts, AlphaFold2-Multimer modeling, and all-atom molecular dynamics simulations together suggest that TDP-43 CR forms dynamic, multimeric helical assemblies stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. These structures show how ALS-associated mutations disrupt TDP-43 function and provide pharmacologically targetable structures to prevent its conversion into pathogenic β-sheet aggregates.

Nature CommunicationsVol. 16(1)
MRC Laboratory of Molecular Biology (GB), Saint Louis University (ES), Brown University (US), Saint Louis University (US), Texas A&M University (US)
U.S. Department of Health and Human Services, Brown University, National Institutes of Health, National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 3%
Amyotrophic Lateral Sclerosis Research
6.95
DOIOpen Access PDFOpenAlex
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