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

Azamat Rizuan, Jayakrishna Shenoy, Priyesh Mohanty, Patricia M. dos Passos, José F. Mercado Ortiz, Leanna Bai, Renjith Viswanathan, Julia Zaborowksy, Szu-Huan Wang, Victoria Johnson, Lohany D. Mamede, Amanda R. Titus, Yuna M. Ayala, Rodolfo Ghirlando, Jeetain Mittal () and Nicolas L. Fawzi ()
Additional contact information
Azamat Rizuan: Texas A&M University, Artie McFerrin Department of Chemical Engineering
Jayakrishna Shenoy: Brown University, Department of Molecular Biology, Cell Biology & Biochemistry
Priyesh Mohanty: Texas A&M University, Artie McFerrin Department of Chemical Engineering
Patricia M. dos Passos: Saint Louis University School of Medicine, Edward Doisy Department of Biochemistry and Molecular Biology
José F. Mercado Ortiz: Brown University, Department of Molecular Biology, Cell Biology & Biochemistry
Leanna Bai: Brown University, Department of Molecular Biology, Cell Biology & Biochemistry
Renjith Viswanathan: Brown University, Department of Molecular Biology, Cell Biology & Biochemistry
Julia Zaborowksy: Brown University, Department of Molecular Biology, Cell Biology & Biochemistry
Szu-Huan Wang: Brown University, Department of Molecular Biology, Cell Biology & Biochemistry
Victoria Johnson: Brown University, Department of Molecular Biology, Cell Biology & Biochemistry
Lohany D. Mamede: Saint Louis University School of Medicine, Edward Doisy Department of Biochemistry and Molecular Biology
Amanda R. Titus: Saint Louis University School of Medicine, Edward Doisy Department of Biochemistry and Molecular Biology
Yuna M. Ayala: Saint Louis University School of Medicine, Edward Doisy Department of Biochemistry and Molecular Biology
Rodolfo Ghirlando: National Institutes of Health, Laboratory of Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases
Jeetain Mittal: Texas A&M University, Artie McFerrin Department of Chemical Engineering
Nicolas L. Fawzi: Brown University, Department of Molecular Biology, Cell Biology & Biochemistry

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65546-w

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