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

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:

• TRA2 protein
• Protein–RNA binding
• molecular modelling
• ligand affinity
• molecular dynamics

Acknowledgements

Authors thank Ms Sony Malhotra for helping PG with the modelling studies. They also thank Dr Abhijit Mitra and Mr Antarip Halder at IIIT, Hyderabad, for helping PG with the quantum mechanical studies.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

We thank University Grants Commission (for funding PG). We thank NCBS (TIFR) for infrastructural facilities. SNG acknowledges the Addison Wheeler Trust and Durham University for funding.