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

Rizuan, Azamat; Shenoy, Jayakrishna; Mohanty, Priyesh; dos Passos, Patricia M. S.; Mercado Ortiz, José F.; Bai, Leanna; Viswanathan, Renjith; Wang, Szu-Huan; Johnson, Victoria; Mamede, Lohany D.; Ayala, Yuna M.; Ghirlando, Rodolfo; Mittal, Jeetain; Fawzi, Nicolas L.

doi:10.1101/2024.07.05.602258

Cited by 3 publications

References 64 publications

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Hydrogen–Deuterium Exchange Mass Spectrometry Reveals Mechanistic Insights into RNA Oligonucleotide-Mediated Inhibition of TDP-43 Aggregation

Minshull,

Byrd,

Olejnik

et al. 2024

J. Am. Chem. Soc.

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Deposits of aggregated TAR DNA-binding protein 43 in the brain are associated with several neurodegenerative diseases. It is well established that binding of RNA/DNA to TDP-43 can prevent TDP-43 aggregation, but an understanding of the structure(s) and conformational dynamics of TDP-43, and TDP-43-RNA complexes, is lacking, including knowledge of how the solution environment modulates these properties. Here, we address this challenge using hydrogen−deuterium exchange-mass spectrometry. In the presence of RNA olignoucleotides, we observe protection from exchange in the RNA recognition motif (RRM) domains of TDP-43 and the linker region between the RRM domains, consistent with nucleic acid binding modulating interdomain interactions. Intriguingly, at elevated salt concentrations, the extent of protection from exchange is reduced in the RRM domains when bound to an RNA sequence derived from the 3′ UTR of the TDP-43 mRNA (CLIP34NT) compared to when bound to a (UG)6 repeat sequence. Under these conditions, CLIP34NT is no longer able to prevent TDP-43 aggregation. This suggests that a salt-induced structural rearrangement occurs when bound to this RNA, which may play a role in facilitating aggregation. Additionally, upon RNA binding, we identify differences in exchange within the short α-helical region located in the C-terminal domain (CTD) of TDP-43. These allosterically altered regions may influence the ability of TDP-43 to aggregate and fine-tune its RNA binding repertoire. Combined, these data provide additional insights into the intricate interplay between TDP-43 aggregation and RNA binding, an understanding of which is crucial for unraveling the molecular mechanisms underlying TDP-43-associated neurodegeneration.

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Hydrogen–Deuterium Exchange Mass Spectrometry Reveals Mechanistic Insights into RNA Oligonucleotide-Mediated Inhibition of TDP-43 Aggregation

Minshull,

Byrd,

Olejnik

et al. 2024

J. Am. Chem. Soc.

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Amino Acid Transfer Free Energies Reveal Thermodynamic Driving Forces in Biomolecular Condensate Formation

Rekhi,

Mittal

2024

Preprint

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The self-assembly of intrinsically disordered proteins into biomolecular condensates shows a dependence on the primary sequence of the protein, leading to sequence-dependent phase separation. Methods to investigate this sequence-dependent phase separation rely on effective residue-level interaction potentials that quantify the propensity for the residues to remain in the dilute phase versus the dense phase. The most direct measure of these effective potentials are the distribution coefficients of the different amino acids between the two phases, but due to the lack of availability of these coefficients, proxies, most notably hydropathy, have been used. However, recent work has demonstrated the limitations of the assumption of hydropathy-driven phase separation. In this work, we address this fundamental gap by calculating the transfer free energies associated with transferring each amino acid side chain analog from the dilute phase to the dense phase of a model biomolecular condensate. We uncover an interplay between favorable protein-mediated and unfavorable water-mediated contributions to the overall free energies of transfer. We further uncover an asymmetry between the contributions of positive and negative charges in the driving forces for condensate formation. The results presented in this work provide an explanation for several non-trivial trends observed in the literature and will aid in the interpretation of experiments aimed at elucidating the sequence-dependent driving forces underlying the formation of biomolecular condensates.

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Progress in the role and mechanism of TDP-43

2024

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Background: TAR DNA-binding protein 43 kDa (TDP-43) has been shown to play an important role in the development of neurodegenerative diseases, but the mechanism is still under study. Methods: By utilizing “TDP43”, “disease”, and “mechanism” as the keywords, 200 related studies were retrieved and downloaded from Pubmed database, including 60 articles. We summarized the progress in understanding TDP-43 mechanism over the past two years, focusing on disease systems and classification of the upstream and downstream, including connection, improvement, and formation. Results: TDP-43, when abnormally aggregated, phosphorylated, or mislocalized, plays a key pathological role in neurodegenerative diseases. Additionally, its impact on normal reproductive cell formation, development, quantity, and activity, as well as insulin secretion and the activation of intestinal epithelial cell necrosis, should not be overlooked. Mechanistically, we identified a relationship between the expression of upstream factors, including Enterovirus D68 (EV-D68), Heterogeneous Nuclear Ribonucleoprotein D (HNRNPD or AUF1), Endoplasmic Reticulum Protein 57 (ERp57), and Progranulin (PGRN), and downstream factors such as Meiotic Recombination Protein Spo11 (Spo11), AMP-Activated Protein Kinase (AMPK), Double-Strand-Break Repair Protein Rad21 Homolog (Rad21L), IκB Kinase (IKK), and TDP-43. Conclusion: TDP-43 plays a pathological role in neurodegeneration, of which, the expression is related to phosphorylation, EV-d68, and HNRNPD.

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

Cited by 3 publications

References 64 publications

Hydrogen–Deuterium Exchange Mass Spectrometry Reveals Mechanistic Insights into RNA Oligonucleotide-Mediated Inhibition of TDP-43 Aggregation

Hydrogen–Deuterium Exchange Mass Spectrometry Reveals Mechanistic Insights into RNA Oligonucleotide-Mediated Inhibition of TDP-43 Aggregation

Amino Acid Transfer Free Energies Reveal Thermodynamic Driving Forces in Biomolecular Condensate Formation

Progress in the role and mechanism of TDP-43

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