An intrinsically disordered RNA-binding region provides local target selectivity and is essential for LARP6 function.

Capraro, F.; Abis, G.; Karimzadeh, M.; Masino, L.; Barley, A.; Bui, T. T. T.; Goodarzi, H.; Conte, M. R.; Mardakheh, F. K.

doi:10.1101/2024.09.20.614075

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bioRxiv · 10.1101/2024.09.20.614075

An intrinsically disordered RNA-binding region provides local target selectivity and is essential for LARP6 function.

Capraro, F.·Abis, G.·Karimzadeh, M.·Masino, L.·Barley, A.·Bui, T. T. T.·Goodarzi, H.·Conte, M. R.·Mardakheh, F. K.

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Abstract

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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Capraro, F., Abis, G., Karimzadeh, M., Masino, L., Barley, A., Bui, T. T. T., Goodarzi, H., Conte, M. R., Mardakheh, F. K.. 2024-09-20. An intrinsically disordered RNA-binding region provides local target selectivity and is essential for LARP6 function.. https://doi.org/10.1101/2024.09.20.614075

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