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

An intrinsically disordered region mediates RNA-binding selectivity and pro-oncogenic activities of LARP6 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article An intrinsically disordered region mediates RNA-binding selectivity and pro-oncogenic activities of LARP6 Faraz Mardakheh, Federica Capraro, Giancarlo Abis, Alessio Incocciati, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6497912/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Feb, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Intrinsically disordered regions (IDRs) are prevalent in RNA-binding proteins (RBPs), yet their roles in RNA interactions remain poorly defined. 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 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. Mechanistically, this is achieved by limiting the conformational flexibility of the adjacent La-module. This 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 through conformational restriction. Biological sciences/Biochemistry/RNA Biological sciences/Biophysics/Intrinsically disordered proteins Biological sciences/Structural biology/SAXS Biological sciences/Structural biology/NMR spectroscopy Biological sciences/Molecular biology/RNA metabolism/RNA transport Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Capraroetal2025SupplementaryInformation.pdf Supplemental Materials Capraroetal2025SupplementalDatasets.xlsx Datasets S1 - S4 Cite Share Download PDF Status: Published Journal Publication published 19 Feb, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6497912","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":450709277,"identity":"9fe4d361-9951-482b-b474-e136571885d1","order_by":0,"name":"Faraz 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