Structure of the Human Core Transcription-export Complex Reveals a Hub for Multivalent Interactions

Overview

Journal Elife

Specialty Biology

Date 2020 Nov 16

PMID 33191911

Citations 28

Authors

Thomas Puhringer

Ulrich Hohmann

Laura Fin

Belen Pacheco-Fiallos

Ulla Schellhaas

Julius Brennecke

Clemens Plaschka

Affiliations

Soon will be listed here.

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.

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References

Kucukelbir A, Sigworth F, Tagare H . Quantifying the local resolution of cryo-EM density maps. Nat Methods. 2013; 11(1):63-5. PMC: 3903095. DOI: 10.1038/nmeth.2727. View

Kumar R, Corbett M, van Bon B, Woenig J, Weir L, Douglas E . THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability. Am J Hum Genet. 2015; 97(2):302-10. PMC: 4573269. DOI: 10.1016/j.ajhg.2015.05.021. View

Xie Y, Ren Y . Mechanisms of nuclear mRNA export: A structural perspective. Traffic. 2019; 20(11):829-840. PMC: 7074880. DOI: 10.1111/tra.12691. View

Shen J, Zhang L, Zhao R . Biochemical characterization of the ATPase and helicase activity of UAP56, an essential pre-mRNA splicing and mRNA export factor. J Biol Chem. 2007; 282(31):22544-50. DOI: 10.1074/jbc.M702304200. View

Strasser K, Hurt E . Yra1p, a conserved nuclear RNA-binding protein, interacts directly with Mex67p and is required for mRNA export. EMBO J. 2000; 19(3):410-20. PMC: 305578. DOI: 10.1093/emboj/19.3.410. View

Tegunov D, Cramer P . Real-time cryo-electron microscopy data preprocessing with Warp. Nat Methods. 2019; 16(11):1146-1152. PMC: 6858868. DOI: 10.1038/s41592-019-0580-y. View

Perez-Calero C, Bayona-Feliu A, Xue X, Barroso S, Munoz S, Gonzalez-Basallote V . UAP56/DDX39B is a major cotranscriptional RNA-DNA helicase that unwinds harmful R loops genome-wide. Genes Dev. 2020; 34(13-14):898-912. PMC: 7328515. DOI: 10.1101/gad.336024.119. View

Cheng H, Dufu K, Lee C, Hsu J, Dias A, Reed R . Human mRNA export machinery recruited to the 5' end of mRNA. Cell. 2006; 127(7):1389-400. DOI: 10.1016/j.cell.2006.10.044. View

Luna R, Rondon A, Perez-Calero C, Salas-Armenteros I, Aguilera A . The THO Complex as a Paradigm for the Prevention of Cotranscriptional R-Loops. Cold Spring Harb Symp Quant Biol. 2020; 84:105-114. DOI: 10.1101/sqb.2019.84.039594. View

10.

Sharif H, Ozgur S, Sharma K, Basquin C, Urlaub H, Conti E . Structural analysis of the yeast Dhh1-Pat1 complex reveals how Dhh1 engages Pat1, Edc3 and RNA in mutually exclusive interactions. Nucleic Acids Res. 2013; 41(17):8377-90. PMC: 3783180. DOI: 10.1093/nar/gkt600. View

11.

Kumar R, Palmer E, Gardner A, Carroll R, Banka S, Abdelhadi O . Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor. Front Mol Neurosci. 2020; 13:12. PMC: 7026477. DOI: 10.3389/fnmol.2020.00012. View

12.

Kohler A, Hurt E . Exporting RNA from the nucleus to the cytoplasm. Nat Rev Mol Cell Biol. 2007; 8(10):761-73. DOI: 10.1038/nrm2255. View

13.

Zenklusen D, Vinciguerra P, Strahm Y, Stutz F . The yeast hnRNP-Like proteins Yra1p and Yra2p participate in mRNA export through interaction with Mex67p. Mol Cell Biol. 2001; 21(13):4219-32. PMC: 87083. DOI: 10.1128/MCB.21.13.4219-4232.2001. View

14.

Kastner B, Fischer N, Golas M, Sander B, Dube P, Boehringer D . GraFix: sample preparation for single-particle electron cryomicroscopy. Nat Methods. 2007; 5(1):53-5. DOI: 10.1038/nmeth1139. View

15.

Casey J, Jenkinson A, Magee A, Ennis S, Monavari A, Green A . Beaulieu-Boycott-Innes syndrome: an intellectual disability syndrome with characteristic facies. Clin Dysmorphol. 2016; 25(4):146-51. DOI: 10.1097/MCD.0000000000000134. View

16.

Sievers F, Wilm A, Dineen D, Gibson T, Karplus K, Li W . Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011; 7:539. PMC: 3261699. DOI: 10.1038/msb.2011.75. View

17.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

18.

Hautbergue G, Hung M, Golovanov A, Lian L, Wilson S . Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP. Proc Natl Acad Sci U S A. 2008; 105(13):5154-9. PMC: 2278192. DOI: 10.1073/pnas.0709167105. View

19.

Ren Y, Schmiege P, Blobel G . Structural and biochemical analyses of the DEAD-box ATPase Sub2 in association with THO or Yra1. Elife. 2017; 6. PMC: 5218534. DOI: 10.7554/eLife.20070. View

20.

Heath C, Viphakone N, Wilson S . The role of TREX in gene expression and disease. Biochem J. 2016; 473(19):2911-35. PMC: 5095910. DOI: 10.1042/BCJ20160010. View