Abstract
SummaryZipcode 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.
Highlights
Zipcode binding protein 1/IGF2 mRNA binding protein 1 (ZBP1/ IGF2BP1/IMP1) is an oncofetal protein expressed at high levels in the embryo that is important for the development of the nervous system
ZBP1 expression is restricted to a small number of tissues and cells, but the protein is expressed at high levels in some cancers, which has been correlated with tumor growth and metastasis (Stohr and Hu€ttelmaier, 2012; Bell et al, 2013)
ZBP1 interacts with a diverse range of mRNA targets (Conway et al, 2016; Patel et al, 2012; Jønson et al, 2007; Hafner et al, 2010; Hansen et al, 2015), and this interaction is important for the stability of the mRNA target and its transport and translational control (Leeds et al, 1997; Conway et al, 2016; Leung et al, 2006; Weidensdorfer et al, 2009; Hu€ttelmaier et al, 2005)
Summary
Zipcode binding protein 1/IGF2 mRNA binding protein 1 (ZBP1/ IGF2BP1/IMP1) is an oncofetal protein expressed at high levels in the embryo that is important for the development of the nervous system. ZBP1 expression is restricted to a small number of tissues and cells, but the protein is expressed at high levels in some cancers, which has been correlated with tumor growth and metastasis (Stohr and Hu€ttelmaier, 2012; Bell et al, 2013). ZBP1 interacts with a diverse range of mRNA targets (Conway et al, 2016; Patel et al, 2012; Jønson et al, 2007; Hafner et al, 2010; Hansen et al, 2015), and this interaction is important for the stability of the mRNA target and its transport and translational control (Leeds et al, 1997; Conway et al, 2016; Leung et al, 2006; Weidensdorfer et al, 2009; Hu€ttelmaier et al, 2005)
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