Structural basis for recognition of diverse localizing mRNAs by Egl-BicD.
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Springer Nature
https://doi.org/10.1038/s41594-026-01794-8
https://doi.org/10.1038/s41594-026-01794-8
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Acknowledgements: We thank members of the A.P.C. and S.L.B. groups for their advice and support and the late D. Ish-Horowicz for long-term encouragement. We are grateful to the Laboratory of Molecular Biology (LMB) EM Facility for access to and support with EM sample preparation and data collection. We thank J. Grimmett, T. Darling and I. Clayson of LMB Scientific Computing for providing resources, the LMB media preparation team for supplying fly food, K. Turton and the LMB Baculovirus Facility for support with insect cell cultures and S. McLaughlin from the LMB Biophysics Facility for assistance with MST measurements. We also acknowledge the Diamond Light Source for access and support of the cryo-EM facilities at the UK’s national Electron Bioimaging Center (proposal bi23268). Work in the A.P.C. and S.L.B. groups is funded by the Medical Research Council as part of UK Research and Innovation (UKRI) (file reference numbers MC_UP_A025_1011 and MC_U105178790, respectively). The work was also supported by a UKRI Biotechnology and Biological Sciences Research Council (BBSRC) project grant to S.L.B. (BB/T00696X/1), a European Molecular Biology Organization postdoctoral fellowship to K.S. (ALTF 197-2021) and a UKRI BBSRC PhD studentship to S.C. (project reference 2273135 as part of BB/M011194/1). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Localization of mRNAs is a widespread mechanism for dictating where proteins operate in cells and underpins many fundamental processes, from embryonic patterning to synaptic plasticity. This spatial control is mediated by the interaction of 'localization signals' in target mRNAs with RNA-binding proteins (RBPs). These signals frequently lack overt sequence or structural patterns, raising the question of how specificity is achieved. Here we investigate this issue using the Drosophila RBP Egalitarian (Egl), which couples mRNAs to microtubule-based transport through Bicaudal D (BicD) and the dynein motor. We present cryo-electron microscopy structures of Egl-BicD bound to six different RNAs. Egl uses multiple noncanonical double-stranded RNA-binding domains to cooperatively form a recognition pocket around localization signals. Despite substantial variation in length and sequence, each signal adopts a bent stem-loop conformation that, together with base-pair identities at two defined sites, drives Egl engagement. We further demonstrate that Egl dimers couple RNA binding to transport initiation through coincident detection of two RNA elements within the same transcript. Thus, localizing mRNAs are recognized through a combination of shape, positional sequence features and number of structured RNA elements. This work reveals a molecular strategy by which diverse mRNAs can be selectively engaged by a single RBP.
Localization of mRNAs is a widespread mechanism for dictating where proteins operate in cells and underpins many fundamental processes, from embryonic patterning to synaptic plasticity. This spatial control is mediated by the interaction of 'localization signals' in target mRNAs with RNA-binding proteins (RBPs). These signals frequently lack overt sequence or structural patterns, raising the question of how specificity is achieved. Here we investigate this issue using the Drosophila RBP Egalitarian (Egl), which couples mRNAs to microtubule-based transport through Bicaudal D (BicD) and the dynein motor. We present cryo-electron microscopy structures of Egl-BicD bound to six different RNAs. Egl uses multiple noncanonical double-stranded RNA-binding domains to cooperatively form a recognition pocket around localization signals. Despite substantial variation in length and sequence, each signal adopts a bent stem-loop conformation that, together with base-pair identities at two defined sites, drives Egl engagement. We further demonstrate that Egl dimers couple RNA binding to transport initiation through coincident detection of two RNA elements within the same transcript. Thus, localizing mRNAs are recognized through a combination of shape, positional sequence features and number of structured RNA elements. This work reveals a molecular strategy by which diverse mRNAs can be selectively engaged by a single RBP.