Insights into HIV-1 proviral transcription from the structure and dynamics of the Tat:AFF4:P-TEFb:TAR complex
- University of California, Berkeley, United States
- University of California, San Francisco, United States
Abstract
HIV-1 Tat hijacks the human superelongation complex (SEC) to promote proviral transcription. Here we report the 5.9 Å structure of HIV-1 TAR in complex with HIV-1 Tat and human AFF4, CDK9, and CycT1. The TAR central loop contacts the CycT1 Tat-TAR recognition motif (TRM) and the second Tat Zn2+-binding loop. Hydrogen-deuterium exchange (HDX) shows that AFF4 helix 2 is stabilized in the TAR complex despite not touching the RNA, explaining how it enhances TAR binding to the SEC 50-fold. RNA SHAPE and SAXS data were used to help model the extended (Tat Arginine-Rich Motif) ARM, which enters the TAR major groove between the bulge and the central loop. The structure and functional assays collectively support a bipartite model, wherein the TAR central loop engages the CycT1 TRM and compact core of Tat, while the TAR major groove interacts with the extended Tat ARM.
Article and author information
Author details
Ignacia Echeverria
Funding
National Institute of General Medical Sciences
- James H Hurley
National Institute of Allergy and Infectious Diseases
- Qiang Zhou
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Axel T Brunger, Stanford University Medical Center, United States
Version history
- Received: March 9, 2016
- Accepted: October 7, 2016
- Accepted Manuscript published: October 12, 2016 (version 1)
- Version of Record published: October 20, 2016 (version 2)
- Version of Record updated: October 21, 2016 (version 3)
Copyright
© 2016, Schulze-Gahmen et al.
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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Insights into HIV-1 proviral transcription from the structure and dynamics of the Tat:AFF4:P-TEFb:TAR complex
eLife 5:e15910.
https://doi.org/10.7554/eLife.15910
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