title: 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.
authors.affiliation: a National Centre for Biological Sciences , Tata Institute of Fundamental Research , GKVK Campus, Bellary Road, Bangalore 560065 , Karnataka , India.
authors.forename: Pritha
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: b School of Biological and Biomedical Sciences , Durham University , Durham , UK.
authors.forename: Sushma Nagaraja
authors.initials: SN
authors.lastname: Grellscheid
authors.affiliation: a National Centre for Biological Sciences , Tata Institute of Fundamental Research , GKVK Campus, Bellary Road, Bangalore 560065 , Karnataka , India.
authors.forename: R
authors.initials: R
authors.lastname: Sowdhamini
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008024:Ligands; D051916:Membrane Cofactor Protein / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D021122:Protein Subunits / Q000737:chemistry; D012313:RNA / Q000737:chemistry*; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C497857:CD46 protein, human; D008024:Ligands; D051916:Membrane Cofactor Protein; D021122:Protein Subunits; D016601:RNA-Binding Proteins; D012313:RNA
keywords: Protein–RNA binding; TRA2 protein; ligand affinity; molecular dynamics; molecular modelling