An intrinsically disordered region mediates RNA-binding selectivity and cellular activities of LARP6
More about Open Access at the CrickAuthors list
Federica Capraro Giancarlo Abis Alessio Incocciati Peter J Simpson Mehran Karimzadeh Laura Masino Alexander Barley Tam TT Bui Geoff Kelly Hani Goodarzi Maria R Conte Faraz K MardakhehAbstract
Intrinsically disordered regions (IDRs) are prevalent in RNA-binding proteins (RBPs), yet their roles in RNA interactions remain poorly defined. We examined RNA-binding regulation by structured and disordered regions of LARP6, an RBP with a diverse RNA-binding repertoire. Mass spectrometry-based RNA interaction mapping in living cells identified direct LARP6-RNA contacts within the structured La-module and its flanking IDRs. Mutagenesis and individual-nucleotide resolution UV-crosslinking and immunoprecipitation (iCLIP) revealed the La-module, but not the IDRs, as essential for LARP6 RNA binding. Deletion of the N-terminal IDR broadened LARP6 RNA footprints, uncovering a role in RNA-binding selectivity. This is achieved through a composite mechanism of restricting the conformational flexibility of the adjacent La-module, forming auxiliary contacts with the RNA, and modulating RNA access for binding. The IDR-mediated RNA-binding selectivity is critical for LARP6-mediated promotion of cancer cell viability and invasion. Our findings uncover a previously unrecognised critical function for IDRs in promoting selective RBP-RNA recognition, by affecting the binding specificity of their adjacent structured domains.
Journal details
Journal
Nature Communications
Pages
Epub ahead of print
Available online
Publication date
Full text links
Publisher website (DOI)
10.1038/s41467-026-69789-z
Europe PubMed Central
41714637
Pubmed
41714637
Keywords
Type of publication
