Abstract
The nuclear export of mRNA represents a critical regulatory node in eukaryotic gene expression. This process is orchestrated by two conserved multi-subunit assemblies: the transcription-and-export complex (TREX) and TREX-2. While TREX facilitates mRNP packaging through multivalent RNA-protein interactions, the precise mechanism by which TREX-2 contributes to mRNA export has remained elusive. Here, we report a functional interaction between UAP56 and TREX-2 and resolve the structures of TREX-2 in both apo and UAP56-bound states. UAP56 engages TREX-2 via its N-terminal region, positioning its RecA domains on the V-shaped surface of the complex. A conserved loop from TREX-2 inserts between the RecA domains of UAP56, stabilizing an open conformation. Biochemical assays demonstrate that TREX-2 significantly stimulates the ATPase activity of UAP56, thereby promoting RNA release. These findings provide structural and mechanistic insights into TREX-2-mediated regulation of mRNA export through UAP56 remodeling.
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Data availability
The atomic coordinates for human TREX-2M and UAP56-TREX-2M have been deposited in the Protein Data Bank (https://www.rcsb.org/search) under the accession codes 9UPC and 9UPB, respectively. The cryo-EM maps for TREX-2M and UAP56-TREX-2M have been deposited in the EMDB with accession codes EMD-64391 and EMD-64390, respectively. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository74 with the dataset identifier PXD068408. Source data are provided with this paper.
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Acknowledgements
We thank the Cryo-EM Center at the University of Science and Technology of China for facility access and technical assistance. We also acknowledge the Core Facility Center for Life Sciences for facility access. This work was supported by funds from the National Natural Science Foundation of China (32471302 to X.Z.), the Natural Science Foundation of Anhui Province (2408085MC068 to X.Z.), the Research Funds of the Center for Advanced Interdisciplinary Science and Biomedicine of IHM (QYPY20230023 to X.Z.), the USTC Research Funds of the Double First-Class Initiative (YD9100002059 to X.Z.), and the Major Program of Shenzhen Bay Laboratory (C1012523007).
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X.G., R.T., H.Z., M.L., and Y.C. designed and performed all the experiments. X.G. and Y.G. prepared cryo-EM samples and collected the cryo-EM data. Xiaofei G., X.Z., and J.H. processed the cryo-EM data, calculated the cryo-EM map, and built the atomic model. All authors contributed to data analysis. X.Z. supervised the project and wrote the manuscript.
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Gong, X., Tao, R., Ge, X. et al. Molecular insights into mRNA export regulation by the human TREX-2 complex. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70088-w
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DOI: https://doi.org/10.1038/s41467-026-70088-w
