A Structural Network Analysis of Neuronal ArhGAP21/23 Interactors by Computational Modeling

Kouchi, Zen; Kojima, Masaki

doi:10.1021/acsomega.2c08054

Cited by 2 publications

References 93 publications

(268 reference statements)

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Neutrophil-specific interactome of ARHGAP25 reveals novel partners and regulatory insights

Sasvári,

Pettkó-Szandtner,

Wisniewski

et al. 2024

Sci Rep

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ARHGAP25, a crucial molecule in immunological processes, serves as a Rac-specific GTPase-activating protein. Its role in cell migration and phagocyte functions, affecting the outcome of complex immunological diseases such as rheumatoid arthritis, renders it a promising target for drug research. Despite its importance, our knowledge of its intracellular interactions is still limited. This study employed proteomic analysis of glutathione S-transferase (GST)-tag pulldowns and co-immunoprecipitation from neutrophilic granulocyte cell lysate, revealing 76 candidates for potential physical interactions that complement ARHGAP25’s known profile. Notably, four small GTPases (RAC2, RHOG, ARF4, and RAB27A) exhibited high affinity for ARHGAP25. The ARHGAP25–RAC2 and ARHGAP25–RHOG interactions appeared to be affected by the activation state of the small GTPases, suggesting a GTP–GDP cycle-dependent interaction. In silico dimer prediction pinpointed ARHGAP25’s GAP domain as a credible binding interface, suggesting its suitability for GTP hydrolysis. Additionally, a list of Fc receptor-related kinases, phosphatases, and three of the 14-3-3 members were identified as potential partners, with in silico predictions highlighting eight binding sites, presenting novel insight on a potential regulatory mechanism for ARHGAP25.

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Neutrophil-specific interactome of ARHGAP25 reveals novel partners and regulatory insights

Sasvári,

Pettkó-Szandtner,

Wisniewski

et al. 2024

Sci Rep

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Gene expression and alternative splicing analysis in a large-scale Multiple Sclerosis study

Sak,

Chariker,

Park

et al. 2024

Preprint

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Background: Multiple Sclerosis (MS) is an autoimmune neurodegenerative disease affecting approximately 3 million people globally. Despite rigorous research on MS, aspects of its development and progression remain unclear. Understanding molecular mechanisms underlying MS is crucial to providing insights into disease pathways, identifying potential biomarkers for early diagnosis, and revealing novel therapeutic targets for improved patient outcomes. Methods: We utilized publicly available RNA-seq data (GSE138614) from post-mortem white matter tissues of five donors without any neurological disorder and ten MS patient donors. This data was interrogated for differential gene expression, alternative splicing and single nucleotide variants as well as for functional enrichments in the resulting datasets. Results: A comparison of non-MS white matter (WM) to MS samples yielded differentially expressed genes involved in adaptive immune response, cell communication, and developmental processes. Genes with expression changes positively correlated with tissue inflammation were enriched in the immune system and receptor interaction pathways. Negatively correlated genes were enriched in neurogenesis, nervous system development, and metabolic pathways. Alternatively spliced transcripts between WM and MS lesions included genes that play roles in neurogenesis, myelination, and oligodendrocyte differentiation, such as brain enriched myelin associated protein (BCAS1), discs large MAGUK scaffold protein 1 (DLG1), KH domain containing RNA binding (QKI), and myelin basic protein (MBP). Our approach to comparing normal appearing WM (NAWM) and active lesion (AL) from one donor and NAWM and chronic active (CA) tissues from two donors, showed that different IgH and IgK gene subfamilies were differentially expressed. We also identified pathways involved in white matter injury repair and remyelination in these tissues. Differentially spliced genes between these lesions were involved in axon and dendrite structure stability. We also identified exon skipping events and spontaneous single nucleotide polymorphisms in membrane associated ring-CH-type finger 1 (MARCHF1), UDP glycosyltransferase 8 (UGT8), and other genes important in autoimmunity and neurodegeneration. Conclusion: Overall, we identified unique genes, pathways, and novel splicing events affecting disease progression that can be further investigated as potential novel drug targets for MS treatment.

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A Structural Network Analysis of Neuronal ArhGAP21/23 Interactors by Computational Modeling

Cited by 2 publications

References 93 publications

Neutrophil-specific interactome of ARHGAP25 reveals novel partners and regulatory insights

Neutrophil-specific interactome of ARHGAP25 reveals novel partners and regulatory insights

Gene expression and alternative splicing analysis in a large-scale Multiple Sclerosis study

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