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<p>TAR DNA-binding protein 43 (TDP-43) is a critical human protein involved in RNA metabolism, encompassing processes such as splicing, stability, and transport. It plays a key role in maintaining physiological functions. Dysregulation of TDP-43 has been implicated in neurodegenerative disorders including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Although several structural studies on TDP-43 have been conducted, comprehensive domain-specific investigations remain limited, especially regarding therapeutic targeting strategies. This study revisits the structural and functional characterization of the RRM domains of TDP-43 using an integrated structural bioinformatics pipeline. We employed advanced tools such as PyMOL for primary structural visualization, RCSB PDB for secondary structure analysis, and PROCHECK for stereochemical evaluation via Ramachandran plot. The Swiss-Model platform facilitated homologous structure modeling, while STRING and Cytoscape were used to construct and analyze protein interaction networks. Importantly, we introduce a domain-specific ligand exploration strategy, using resolved 3D domain structures of TDP-43 to identify potential therapeutic targets. This integrative analysis not only consolidates previous findings but also introduces a refined approach to targeting individual domains of TDP-43. These insights may contribute to the development of more specific and effective therapeutic interventions for TDP-43-associated neurodegenerative diseases.</p>

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Comprehensive study of TDP-43 protein through NMR assignment and structural analysis

  • 期刊论文

  • 发表日期：

    2025年7月14日

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  • Harshit Singh,
  • Vivek Srivastava

摘要

TAR DNA-binding protein 43 (TDP-43) is a critical human protein involved in RNA metabolism, encompassing processes such as splicing, stability, and transport. It plays a key role in maintaining physiological functions. Dysregulation of TDP-43 has been implicated in neurodegenerative disorders including frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Although several structural studies on TDP-43 have been conducted, comprehensive domain-specific investigations remain limited, especially regarding therapeutic targeting strategies. This study revisits the structural and functional characterization of the RRM domains of TDP-43 using an integrated structural bioinformatics pipeline. We employed advanced tools such as PyMOL for primary structural visualization, RCSB PDB for secondary structure analysis, and PROCHECK for stereochemical evaluation via Ramachandran plot. The Swiss-Model platform facilitated homologous structure modeling, while STRING and Cytoscape were used to construct and analyze protein interaction networks. Importantly, we introduce a domain-specific ligand exploration strategy, using resolved 3D domain structures of TDP-43 to identify potential therapeutic targets. This integrative analysis not only consolidates previous findings but also introduces a refined approach to targeting individual domains of TDP-43. These insights may contribute to the development of more specific and effective therapeutic interventions for TDP-43-associated neurodegenerative diseases.