IDRM Seminar Series: The interplay of multivalent signatures in the assembly of protein-RNA complexes

RNA binding proteins are rich in intrinsically disordered regions (IDRs) that form multivalent contacts to support formation of higher-order ribonucleoprotein (RNP) condensates. Moreover, multivalent RNA signatures also contribute to assembly of such RNP condensates. To assess the interplay of both types of signatures, we improved the individual nucleotide resolution CLIP protocol (iiCLIP) to produce highly sensitive and specific data, and thus enable quantitative comparisons of interactions across conditions (Lee et al., 2021). We also developed software for discovery and visualisation of multivalent RNA binding motifs from CLIP data (Kuret et al, 2021). This enabled us to show that the IDR-dependent condensation properties of TDP-43 interplay with dispersed-multivalent RNA motifs to specify its RNA binding and regulatory repertoire (Hallegger et al., 2021). IDRs are also the predominant sites of post-translational modifications in RBPs, and so we asked how a signalling pathway can act on an IDR to modify RNA-binding specificity of an RBP to alter its regulatory network and thereby drive a developmental transition. We focused on the MEK/ERK-induced phosphorylation of the IDR in LIN28A, to find that this drives its nucleocytoplasmic translocation and a major transcriptome-wide convergence towards the 3’ UTR termini of mRNAs. Such convergent RNA binding of phosphorylated LIN28A selects mRNAs for decay, and how this ensures coordination between pluripotency progression and morphogenesis. These studies demonstrate an intricate and highly dynamic interplay between multivalent signatures in RNAs and proteins in the dynamic assembly and functions of RNPs.

References: Hallegger, M., Chakrabarti, A.M., Lee, F.C.Y., Lee, B.L., Amalietti, A.G., Odeh, H.M., Copley, K.E., Rubien, J.D., Portz, B., Kuret, K., et al. (2021). TDP-43 condensation properties specify its RNA-binding and regulatory repertoire. Cell 184, 4680–4696.e22.

Kuret, K., Amalietti, A.G., and Ule, J. (2021). Positional motif analysis reveals the extent of specificity of protein-RNA interactions observed by CLIP. bioRxiv.

Lee, F.C.Y., Chakrabarti, A.M., Hänel, H., Monzón-Casanova, E., Hallegger, M., Militti, C., Capraro, F., Sadée, C., Toolan-Kerr, P., Wilkins, O., et al. (2021). An improved iCLIP protocol. bioRxiv