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Molecular basis of selectivity in Syncrip’s recognition of target RNAs

Gronland, Glen Robert; (2021) Molecular basis of selectivity in Syncrip’s recognition of target RNAs. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The highly-conserved RNA-binding protein Syncrip is an important post-transcriptional regulator of gene expression, playing a pivotal role in neuronal and muscular development during mammalian and Drosophila embryogenesis. Syncrip’s biological functions are enabled through its combinatorial usage of multiple RNA-binding domains to modulate the stability, transport and translation of a diverse, yet functionally distinct, set of RNA targets. While a number of physiological targets and targets sequences have been identified, it is still poorly understood how Syncrip selects and binds these specific RNAs at the structural and molecular level. In this thesis I ask how Syncrip is able to recognise different RNAs through the use of multiple RNA-binding modes, focusing on poly(A) RNA sequences and miR-3470 as model systems which are linked to Syncrip’s roles in the translational repression of mRNAs and the exosomal loading of miRNAs, respectively. I have found that each RNA-binding mode is characterised by different relative domain contributions to the overall specificity and affinity of either interaction. Importantly, this is underpinned by inter-domain interactions and dynamics which are associated with the formation of composite RNA-binding surfaces, as well as the definition of binding registers. Moreover, I have obtained structural information on Syncrip bound to poly(A) RNA and miR-3470, which lays the groundwork for the complete resolution of the domain arrangement in either RNA complex. The data presented here provides valuable insight into the different RNA-binding mechanisms utilised by Syncrip, which serves to expand our understanding of the molecular basis of selectivity in the protein’s recognition of target RNAs. This will hopefully guide future studies on Syncrip, particularly those that investigate its prospective role as a global repressor of translation, and the medical potential of the mechanism behind the loading of specific RNAs into exosomes.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Molecular basis of selectivity in Syncrip’s recognition of target RNAs
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10133481
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