A tale of two paralogs: human Transformer2 proteins with differential RNA-binding affinities

J Biomol Struct Dyn. 2016 Sep;34(9):1979-86. doi: 10.1080/07391102.2015.1100551. Epub 2015 Nov 26.

Abstract

The Transformer2 (Tra2) proteins in humans are homologues of the Drosophila Tra2 protein. One of the two RNA-binding paralogs, Tra2β, has been very well-studied over the past decade, but not much is known about Tra2α. It was very recently shown that the two proteins demonstrate the phenomenon of paralog compensation. Here, we provide a structural basis for this genetic backup circuit, using molecular modelling and dynamics studies. We show that the two proteins display similar binding specificities, but differential affinities to a short GAA-rich RNA stretch. Starting from the 6-nucleotide RNA in the solution structure, close to 4000 virtual mutations were modelled on RNA and the domain-RNA interactions were studied after energy minimisation to convergence. Separately, another known 13-nucleotide stretch was docked and the domain-RNA interactions were observed through a 100-ns dynamics trajectory. We have also demonstrated the 'compensatory' mechanism at the level of domains in one of the domain repeat-containing RNA-binding proteins.

Keywords: Protein–RNA binding; TRA2 protein; ligand affinity; molecular dynamics; molecular modelling.

MeSH terms

  • Amino Acid Sequence
  • Humans
  • Ligands
  • Membrane Cofactor Protein / chemistry*
  • Membrane Cofactor Protein / metabolism
  • Models, Molecular*
  • Nucleic Acid Conformation
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Protein Subunits / chemistry
  • RNA / chemistry*
  • RNA-Binding Proteins / chemistry*
  • RNA-Binding Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • CD46 protein, human
  • Ligands
  • Membrane Cofactor Protein
  • Protein Subunits
  • RNA-Binding Proteins
  • RNA