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April 15th, 2025
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Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK.
biochemistry
biorxiv

An intrinsically disordered region mediates RNA-binding selectivity and pro-oncogenic activities of LARP6

Capraro, F.Open in Google Scholar•Abis, G.Open in Google Scholar•Incocciati, A.Open in Google Scholar•Karimzadeh, M.Open in Google Scholar•Masino, L.Open in Google Scholar•Barley, A.Open in Google Scholar•Bui, T. T. T.Open in Google Scholar•Kelly, G.Open in Google Scholar•Goodarzi, H.Open in Google Scholar•Conte, M. R.Open in Google Scholaret al.

Intrinsically disordered regions (IDRs) are prevalent in RNA-binding proteins (RBPs), yet their roles in RNA interactions remain poorly defined. Here, we examined the structured and disordered RNA-binding activities of LARP6, an RBP with a diverse RNA-binding repertoire. Using mass spectrometry-based RNA interaction mapping in living cells, we identified direct LARP6-RNA contacts within both the structured La-module and its flanking IDRs. Mutagenesis combined with individual-nucleotide resolution UV crosslinking and immunoprecipitation (iCLIP) revealed the La-module, but not the IDRs, as essential for LARP6 binding to RNA. Deletion of the N-terminal IDR broadened the footprints of LARP6 on RNA, uncovering a role in RNA-binding selectivity. Mechanistically, this is achieved through restricting the conformational flexibility of the adjacent La-module. The IDR-mediated RNA-binding selectivity is critical for LARP6-driven cancer cell viability and invasion. Our findings uncover a previously unrecognised critical function for IDRs in promoting selective RBP-RNA interactions, which operates through conformational restriction.

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