The structural basis for RNA selectivity by the IMP family of RNA binding proteins

Abstract

The Igf2 mRNA binding proteins (ZBP1/IMP1, IMP2, IMP3) are highly conserved posttranscriptional regulators of RNA stability, localization and translation. They play important roles in cell migration, neural development, metabolism and cancer cell survival. The knockout phenotypes of individual IMP proteins suggest that each family member regulates a unique pool of RNAs, yet evidence and an underlying mechanism for this is lacking. Here, we combine SELEX and NMR spectroscopy to demonstrate that the major RNA binding domains of the two most distantly related IMPs (ZBP1 and IMP2) bind to different consensus sequences and regulate targets consistent with their knockout phenotypes and roles in disease. We find that the targeting specificity of each IMP is determined by few amino acids in their variable loops. As variable loops often differ amongst KH domain paralogs, we hypothesize that this is a general mechanism for evolving specificity and regulation of the transcriptome.3 Introduction:

Structures and target RNA preferences of the RNA-binding protein family of IGF2BPs: An overview

“…Although the zipcode-like orientation of motifs seems preferred, both polarities are tolerated. In contrast, KH3-4 of IMP2 interacts with a 5 0 -CUCA(C/G)-N 9-12nt -(A/U)GG(A/U)-3 0 motif, but, unlike IMP1 and 3, preferably in an N-C orientation (Biswas et al, 2019b). The striking similarity though is a preference of KH3 to a CA-rich motif with weak nucleotide discrimination, whereas KH4 contacts motifs with a central GG, while domains have to be appropriately spaced (Biswas et al, 2019a;Nicastro et al, 2017;Patel et al, 2012;Schneider et al, 2019).…”

“…However, they incompletely reflect the expectable complexity of RNA sequences recognized by the six RBDs, one tandem RRM, and two tandem heterogeneous nuclear ribonucleoprotein (hnRNP) K-homology (KH) domains. Over the last decade, expert laboratories have advanced the structurebased examination of specificity of individual domains for RNA motifs (Biswas et al, 2019b;Chao et al, 2010;Dagil et al, 2019;Jia et al, 2018;Nicastro et al, 2017;Schneider et al, 2019). Findings were put into context of the overall recognition of target mRNAs and the structure-based differences between members of the IMP protein family.…”

An oncopeptide regulates m6A recognition by the m6A reader IGF2BP1 and tumorigenesis

“…Thus, we termed the LINC00266-1-encoded peptide RBRP. The RNA-binding protein, RNA m6A reader IGF2BP1, was particularly interesting, because the protein score of IGF2BP1 was TOP5 in the identified RBRP interactors, RNA m 6 A modification play an important role in the hallmark of cancer, and IGF2BP1 regulates the level of an important oncogene c-Myc and tumorigenesis 6,19,20 , consistent with the oncogenic roles of RBRP in tumorigenesis. Therefore, we here select IGF2BP1 for further investigation.…”

Increased expression of the RNA‑binding motif protein 47�predicts poor prognosis in non‑small‑cell lung cancer

“…In addition, it was identified as a novel biomarker and an independent prognostic marker (40). In addition to protein expression levels, the biological functions of RBPs are varied, including RNA alternative splicing, stability, subcellular localization and translation (41,42). The roles of RBPs in cancer can therefore be diverse.…”