Combinatorial recognition of clustered RNA elements by the multidomain RNA-binding protein IMP3

Tim Schneider, Lee-Hsueh Hung, Masood Aziz, Anna Wilmen, Stephanie Thaum, Jacqueline Wagner, Robert Janowski, Simon Müller, Silke Schreiner, Peter Friedhoff, Stefan Hüttelmaier, Dierk Niessing, Michael Sattler (), Andreas Schlundt () and Albrecht Bindereif ()
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Tim Schneider: Justus-Liebig-University of Giessen
Lee-Hsueh Hung: Justus-Liebig-University of Giessen
Masood Aziz: Technical University of Munich (TUM)
Anna Wilmen: Justus-Liebig-University of Giessen
Stephanie Thaum: Justus-Liebig-University of Giessen
Jacqueline Wagner: Technical University of Munich (TUM)
Robert Janowski: Helmholtz-Zentrum München
Simon Müller: Martin Luther University Halle-Wittenberg
Silke Schreiner: Justus-Liebig-University of Giessen
Peter Friedhoff: Justus-Liebig-University of Giessen
Stefan Hüttelmaier: Martin Luther University Halle-Wittenberg
Dierk Niessing: Helmholtz-Zentrum München
Michael Sattler: Technical University of Munich (TUM)
Andreas Schlundt: Technical University of Munich (TUM)
Albrecht Bindereif: Justus-Liebig-University of Giessen

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract How multidomain RNA-binding proteins recognize their specific target sequences, based on a combinatorial code, represents a fundamental unsolved question and has not been studied systematically so far. Here we focus on a prototypical multidomain RNA-binding protein, IMP3 (also called IGF2BP3), which contains six RNA-binding domains (RBDs): four KH and two RRM domains. We establish an integrative systematic strategy, combining single-domain-resolved SELEX-seq, motif-spacing analyses, in vivo iCLIP, functional validation assays, and structural biology. This approach identifies the RNA-binding specificity and RNP topology of IMP3, involving all six RBDs and a cluster of up to five distinct and appropriately spaced CA-rich and GGC-core RNA elements, covering a >100 nucleotide-long target RNA region. Our generally applicable approach explains both specificity and flexibility of IMP3-RNA recognition, allows the prediction of IMP3 targets, and provides a paradigm for the function of multivalent interactions with multidomain RNA-binding proteins in gene regulation.

Date: 2019
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DOI: 10.1038/s41467-019-09769-8

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