The export receptor Crm1 forms a dimer to promote nuclear export of HIV RNA

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Abstract

The HIV Rev protein routes viral RNAs containing the Rev Response Element (RRE) through the Crm1 nuclear export pathway to the cytoplasm where viral proteins are expressed and genomic RNA is delivered to assembling virions. The RRE assembles a Rev oligomer that displays nuclear export sequences (NESs) for recognition by the Crm1-Ran^GTP nuclear receptor complex. Here we provide the first view of an assembled HIV-host nuclear export complex using single-particle electron microscopy. Unexpectedly, Crm1 forms a dimer with an extensive interface that enhances association with Rev-RRE and poises NES binding sites to interact with a Rev oligomer. The interface between Crm1 monomers explains differences between Crm1 orthologs that alter nuclear export and determine cellular tropism for viral replication. The arrangement of the export complex identifies a novel binding surface to possibly target an HIV inhibitor and may point to a broader role for Crm1 dimerization in regulating host gene expression.

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David S Booth

Graduate Group in Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Yifan Cheng

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Alan D Frankel

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States

For correspondence
frankel@cgl.ucsf.edu

Competing interests
The authors declare that no competing interests exist.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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David S Booth
Yifan Cheng
Alan D Frankel

(2014)

The export receptor Crm1 forms a dimer to promote nuclear export of HIV RNA

eLife 3:e04121.

https://doi.org/10.7554/eLife.04121

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Research organisms

Human
Virus

1. Biochemistry and Chemical Biology
2. Microbiology and Infectious Disease
RNA-directed remodeling of the HIV-1 protein Rev orchestrates assembly of the Rev–Rev response element complex

Bhargavi Jayaraman, David C Crosby ... Alan D Frankel

Research Article Updated Jan 9, 2015
The HIV-1 protein Rev controls a critical step in viral replication by mediating the nuclear export of unspliced and singly-spliced viral mRNAs. Multiple Rev subunits assemble on the Rev Response Element (RRE), a structured region present in these RNAs, and direct their export through the Crm1 pathway. Rev-RRE assembly occurs via several Rev oligomerization and RNA-binding steps, but how these steps are coordinated to form an export–competent complex is unclear. Here, we report the first crystal structure of a Rev dimer-RRE complex, revealing a dramatic rearrangement of the Rev-dimer upon RRE binding through re-packing of its hydrophobic protein–protein interface. Rev-RNA recognition relies on sequence-specific contacts at the well-characterized IIB site and local RNA architecture at the second site. The structure supports a model in which the RRE utilizes the inherent plasticity of Rev subunit interfaces to guide the formation of a functional complex.
1. Microbiology and Infectious Disease
Rev Protein: Really exasperating viral protein from HIV

James R Williamson

Insight Jan 9, 2015
Two new structures shed additional light on the nuclear transport of viral transcripts.
1. Computational and Systems Biology
2. Structural Biology and Molecular Biophysics
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