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bioRxiv · 10.1101/2024.07.16.603833

BLM Aggregation-Prone Ability and Similarity to Intrinsically Disordered Proteins Indicate its Potential Role in Neurodegenerative Diseases

Sharma, S.·Yadav, S. S.·Nair, R. R.
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Abstract

BLM helicase is a member of the RecQ family of DNA helicases, enzymes that play a critical role in maintaining genome stability. The BLM protein is named after Bloom syndrome (BS), a rare genetic disorder caused by mutations in the helicase domain of BLM gene. BLM role has mostly been studied in DNA repair, replication, and recombination; however, a recent study has highlighted the RNA binding capability of the BLM protein. Several proteins, including TDP43, Tau, and alpha-synuclein, are known to play key roles in neurodegenerative diseases. These proteins possess residues prone to parallel aggregation and fibril formation, the key contributor to neurodegenerative disease development. We utilized various in-silico tools like PASTA 2.0, SIFT, PolyPhen 2, and PhD SNP, SNP&GO, Meta-SNP, and SNAP, etc., to identify the molecular signature of the BLMs protein. Our in-silico analysis suggests that the BLMs HRDC domain has ability of parallel aggregation and fibril formation. Moreover, structural similarity with proteins like -synuclein, TDP-43, and Tau and its interactions with PARP1 suggests it may have a role in neurodegenerative diseases. Furthermore, we identified deleterious mutations in the HRDC domain of BLM protein that may compromise its stability and alter its function. Hence, these findings suggest that in addition to BLMs well-known functions, the protein may have ability to form parallel aggregation and fibril formation and its role in neurodegenerative disease need to further be explored. Author SummaryThis paper higlights the importance of considering the structural and physical characteristics of the BLM protein, which may have been previously overlooked in the context of disease pathology. Through in-silico analyses, we identified that the BLM protein possesses residues within the HRDC domain that are prone to parallel aggregation and fibril formation. Moreover, the structural similarity of BLM to proteins such as -synuclein, TDP-43, and Tau indicates a potential role for BLM in neurodegenerative processes. Additionally, we identified deleterious mutations within the HRDC domain that could compromise the stability of the protein. Furthermore, our findings suggest that the association between BLM and PARP1 may involve a regulatory mechanism that could significantly influence BLMs function.

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Sharma, S., Yadav, S. S., Nair, R. R.. 2024-07-19. BLM Aggregation-Prone Ability and Similarity to Intrinsically Disordered Proteins Indicate its Potential Role in Neurodegenerative Diseases. https://doi.org/10.1101/2024.07.16.603833

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