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Insights into HIV-1 proviral transcription from integrative structure and dynamics of the Tat:AFF4:P-TEFb:TAR complex

Journal Article · · eLife
DOI:https://doi.org/10.7554/elife.15910· OSTI ID:1628854
 [1];  [2];  [3];  [4];  [4];  [5];  [6];  [4];  [5];  [3]
  1. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Univ. of California, Berkeley, CA (United States). California Inst. of Quantitative Biosciences; DOE/OSTI
  2. Univ. of California, San Francisco, CA (United States). Dept. of Bioengineering and Therapeutic Sciences; Univ. of California, San Francisco, CA (United States). Dept. of Pharmaceutical Chemistry; Univ. of California, San Francisco, CA (United States). California Inst. of Quantitative Biosciences
  3. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Univ. of California, Berkeley, CA (United States). California Inst. of Quantitative Biosciences; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division
  4. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Univ. of California, Berkeley, CA (United States). California Inst. of Quantitative Biosciences
  5. Univ. of California, San Francisco, CA (United States). Dept. of Bioengineering and Therapeutic Sciences; Univ. of California, San Francisco, CA (United States). Dept. of Pharmaceutical Chemistry; Univ. of California, San Francisco, CA (United States). California Inst. of Quantitative Biosciences
  6. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Univ. of California, Berkeley, CA (United States). California Inst. of Quantitative Biosciences; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division; Univ. of California, Berkeley, CA (United States). Howard Hughes Medical Inst.; Univ. of California, Berkeley, CA (United States). Dept. of Chemistry
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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 an integrative structure and a bipartite binding 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.
Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1628854
Journal Information:
eLife, Journal Name: eLife Vol. 5; ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.Copyright Statement
Country of Publication:
United States
Language:
English

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Cited By (11)

HIV-1 Tat interactions with cellular 7SK and viral TAR RNAs identifies dual structural mimicry journal October 2018
AFF1 acetylation by p300 temporally inhibits transcription during genotoxic stress response journal October 2019
An ultra-high affinity ligand of HIV-1 TAR reveals the RNA structure recognized by P-TEFb journal November 2018
Structure of HIV TAR in complex with a Lab-Evolved RRM provides insight into duplex RNA recognition and synthesis of a constrained peptide that impairs transcription journal June 2018
Cat and Mouse: HIV Transcription in Latency, Immune Evasion and Cure/Remission Strategies journal March 2019
Structural mechanism for HIV-1 TAR loop recognition by Tat and the super elongation complex journal December 2018
Structure of the super-elongation complex subunit AFF4 C-terminal homology domain reveals requirements for AFF homo- and heterodimerization journal May 2019
Cyclin-dependent kinase 7 (CDK7)-mediated phosphorylation of the CDK9 activation loop promotes P-TEFb assembly with Tat and proviral HIV reactivation journal June 2018
Face-time with TAR: Portraits of an HIV-1 RNA with diverse modes of effector recognition relevant for drug discovery journal May 2019
Regulation of cyclin T1 during HIV replication and latency establishment in human memory CD4 T cells journal February 2019
Reiterative Enrichment and Authentication of CRISPRi Targets (REACT) identifies the proteasome as a key contributor to HIV-1 latency journal January 2019

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