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

Nat Commun. 2019 Sep 30;10(1):4440. doi: 10.1038/s41467-019-12193-7.


The IGF2 mRNA-binding proteins (ZBP1/IMP1, IMP2, IMP3) are highly conserved post-transcriptional 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 systematic evolution of ligands by exponential enrichment (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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Mice
  • Models, Molecular
  • Mutation
  • Protein Binding
  • Protein Domains
  • RNA / metabolism*
  • RNA Stability
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / chemistry*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Ribonucleoproteins, Small Nucleolar
  • SELEX Aptamer Technique
  • Transcriptome


  • DNA-Binding Proteins
  • IGF2BP1 protein, human
  • IGF2BP2 protein, human
  • IMP3 protein, human
  • Ligands
  • RNA, Messenger
  • RNA-Binding Proteins
  • Ribonucleoproteins, Small Nucleolar
  • ZBP1 protein, human
  • RNA