Abstract
The export of mRNA from nucleus to cytoplasm requires the conserved and essential transcription and export (TREX) complex (THO-UAP56/DDX39B-ALYREF). TREX selectively binds mRNA maturation marks and licenses mRNA for nuclear export by loading the export factor NXF1-NXT1. How TREX integrates these marks and achieves high selectivity for mature mRNA is poorly understood. Here, we report the cryo-electron microscopy structure of the human THO-UAP56/DDX39B complex at 3.3 Å resolution. The seven-subunit THO-UAP56/DDX39B complex multimerizes into a 28-subunit tetrameric assembly, suggesting that selective recognition of mature mRNA is facilitated by the simultaneous sensing of multiple, spatially distant mRNA regions and maturation marks. Two UAP56/DDX39B RNA helicases are juxtaposed at each end of the tetramer, which would allow one bivalent ALYREF protein to bridge adjacent helicases and regulate the TREX-mRNA interaction. Our structural and biochemical results suggest a conserved model for TREX complex function that depends on multivalent interactions between proteins and mRNA.
Highlights
Eukaryotic protein-coding mRNA is matured in the nucleus before it is exported and translated in the cytoplasm
The transcription and export (TREX) complex is recruited during transcription (Heath et al, 2016; Viphakone et al, 2019) to maturing messenger ribonucleoprotein complexes (mRNPs) through mRNA and protein interactions at the mRNP 5’-end, splice junctions, and mRNP 3’-end (Cheng et al, 2006; Merz et al, 2007; Gromadzka et al, 2016; Shi et al, 2017)
Our results show that THO– UAP56 adopts a tetrameric 28-subunit architecture, suggesting how TREX may bind multiple mRNA and mRNP regions at the same time
Summary
Eukaryotic protein-coding mRNA is matured in the nucleus before it is exported and translated in the cytoplasm. When TREX binds to mRNA, it adds on a final protein which allows the mRNA molecule to be transported out of the nucleus It remained unclear how TREX selects the completed mRNA-protein complexes that are ready for export while at the same time recognizing the wide variety of mRNA molecules produced by cells. The structure suggests that TREX can bind to mRNA and its attached proteins in various ways These different binding arrangements may help the complex select which mRNA molecules are fully modified and ready to be exported. This work will help guide future research into the activity of TREX, including how its structure changes when it binds to mRNA and deposits the final transport protein Identifying these structures will make it easier to design experiments that target specific aspects of TREX activity and provide new insights into how these complexes work. The data reveal a conserved mechanism for TREX function that depends on multivalent protein–mRNA interactions
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