The Francis Crick Institute
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Mechanism of β-actin mRNA recognition by ZBP1

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journal contribution
posted on 2020-10-15, 09:48 authored by Giuseppe Nicastro, Adela M Candel, Michael Uhl, Alain Oregioni, David Hollingworth, Rolf Backofen, Stephen R Martin, Andres Ramos
Zipcode binding protein 1 (ZBP1) is an oncofetal RNA-binding protein that mediates the transport and local translation of β-actin mRNA by the KH3-KH4 di-domain, which is essential for neuronal development. The high-resolution structures of KH3-KH4 with their respective target sequences show that KH4 recognizes a non-canonical GGA sequence via an enlarged and dynamic hydrophobic groove, whereas KH3 binding to a core CA sequence occurs with low specificity. A data-informed kinetic simulation of the two-step binding reaction reveals that the overall reaction is driven by the second binding event and that the moderate affinities of the individual interactions favor RNA looping. Furthermore, the concentration of ZBP1, but not of the target RNA, modulates the interaction, which explains the functional significance of enhanced ZBP1 expression during embryonic development.