Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 14, Pages -Publisher
MDPI
DOI: 10.3390/ijms23147626
Keywords
DBHS; NONO; SFPQ; structural bioinformatics
Funding
- Associazione Italiana Ricerca sul Cancro (AIRC) [IG24365]
- MIUR-Progetto Eccellenza
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Researchers investigated the stability of NONO and SFPQ dimers, finding that heterodimerization is more favorable than homodimer formation; they also found that the RRM2 subunits of NONO and SFPQ are primarily required for protein-protein interactions with other DBHS protomers; their findings could contribute to the design of small molecules to modulate the activity of these proteins.
NONO and SFPQ are involved in multiple nuclear processes (e.g., pre-mRNA splicing, DNA repair, and transcriptional regulation). These proteins, along with NEAT1, enable paraspeckle formation, thus promoting multiple myeloma cell survival. In this paper, we investigate NONO and SFPQ dimer stability, highlighting the hetero- and homodimer structural differences, and model their interactions with RNA, simulating their binding to a polyG probe mimicking NEAT1guanine-rich regions. We demonstrated in silico that NONO::SFPQ heterodimerization is a more favorable process than homodimer formation. We also show that NONO and SFPQ RRM2 subunits are primarily required for protein-protein interactions with the other DBHS protomer. Simulation of RNA binding to NONO and SFPQ, beside validating RRM1 RNP signature importance, highlighted the role of beta 2 and beta 4 strand residues for RNA specific recognition. Moreover, we demonstrated the role of the NOPS region and other protomer's RRM2 beta 2/beta 3 loop in strengthening the interaction with RNA. Our results, having deepened RNA and DBHS dimer interactions, could contribute to the design of small molecules to modulate the activity of these proteins. RNA-mimetics, able to selectively bind to NONO and/or SFPQ RNA-recognition site, could impair paraspeckle formation, thus representing a first step towards the discovery of drugs for multiple myeloma treatment.
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