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RNA binding proteins (RBPs) containing intrinsically disordered regions (IDRs) are present in diverse molecular complexes where they function as dynamic regulators. Their characteristics promote liquid-liquid phase separation (LLPS) and the formation of membraneless organelles such as stress granules and nucleoli. IDR-RBPs are particularly relevant in the nervous system and their dysfunction is associated with neurodegenerative diseases and brain tumor development. Serpine1 mRNA-binding protein 1 (SERBP1) is a unique member of this group, being mostly disordered and lacking canonical RNA-binding domains. We defined SERBP1’s interactome, uncovered novel roles in splicing, cell division and ribosomal biogenesis, and showed its participation in pathological stress granules and Tau aggregates in Alzheimer’s brains. SERBP1 preferentially interacts with other G-quadruplex (G4) binders, implicated in different stages of gene expression, suggesting that G4 binding is a critical component of SERBP1 function in different settings. Similarly, we identified important associations between SERBP1 and PARP1/polyADP-ribosylation (PARylation). SERBP1 interacts with PARP1 and its associated factors and influences PARylation. Moreover, protein complexes in which SERBP1 participates contain mostly PARylated proteins and PAR binders. Based on these results, we propose a feedback regulatory model in which SERBP1 influences PARP1 function and PARylation, while PARylation modulates SERBP1 functions and participation in regulatory complexes.

Serpine mRNA-binding protein 1 (SERBP1) is an intrinsically disordered RNA-binding protein that regulates translation and ribosome biogenesis through interactions with ribosomes and other molecular complexes. Despite its regulatory importance and implication in cancer development, the molecular basis of SERBP1 RNA recognition remains poorly understood. Here, we characterize the G-quadruplex (G4)-binding properties of SERBP1. Using NMR spectroscopy and biophysical assays, we show that SERBP1 binds parallel G4s, both RNA and DNA, with low micromolar affinity through a conserved mechanism. Molecular dynamics and docking simulations reveal an encircling mechanism in which the RGG box wraps around the G4 while downstream C-terminal serine residues stabilize the complex through hydrogen bonding. Phosphomimetic mutations of key serines disrupt this stabilization and reduce binding affinity, identifying phosphorylation as a regulatory switch for SERBP1 activity. Recognition is driven by G4 topology rather than nucleotide sequence, establishing SERBP1 as a broad-specificity G4-binding protein. We further demonstrate that SERBP1 regulates mTOR expression in glioblastoma cell lines through G4 elements in the mTOR 5' UTR, and that SERBP1 depletion synergizes with mTOR inhibition to reduce cell growth. These results establish SERBP1 as a G4 adaptor protein and represent, to our knowledge, the first detailed characterization of G4 recognition by a fully disordered domain, providing a molecular framework for targeting SERBP1-G4 interactions in cancer.

RNA binding proteins (RBPs) containing intrinsically disordered regions (IDRs) are present in diverse molecular complexes where they function as dynamic regulators. Their characteristics promote liquid-liquid phase separation (LLPS) and the formation of membraneless organelles such as stress granules and nucleoli. IDR-RBPs are particularly relevant in the nervous system and their dysfunction is associated with neurodegenerative diseases and brain tumor development. Serpine1 mRNA-binding protein 1 (SERBP1) is a unique member of this group, being mostly disordered and lacking canonical RNA-binding domains. We defined SERBP1’s interactome, uncovered novel roles in splicing, cell division and ribosomal biogenesis, and showed its participation in pathological stress granules and Tau aggregates in Alzheimer’s brains. SERBP1 preferentially interacts with other G-quadruplex (G4) binders, implicated in different stages of gene expression, suggesting that G4 binding is a critical component of SERBP1 function in different settings. Similarly, we identified important associations between SERBP1 and PARP1/polyADP-ribosylation (PARylation). SERBP1 interacts with PARP1 and its associated factors and influences PARylation. Moreover, protein complexes in which SERBP1 participates contain mostly PARylated proteins and PAR binders. Based on these results, we propose a feedback regulatory model in which SERBP1 influences PARP1 function and PARylation, while PARylation modulates SERBP1 functions and participation in regulatory complexes.