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

Ursula Schulze-Gahmen; Ignacia Echeverria; Goran Stjepanovic; Yun Bai; Huasong Lu; Dina Schneidman-Duhovny; Jennifer A. Doudna; Qiang Zhou; Andrej Sali; James H. Hurley

doi:10.7554/eLife.15910

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

Ursula Schulze-Gahmen, Ignacia Echeverria, Goran Stjepanovic, Yun Bai, Huasong Lu, Dina Schneidman-Duhovny, Jennifer A. Doudna, Qiang Zhou, Andrej Sali, James H. Hurley

Research output: Contribution to journal › Article › peer-review

Abstract

HIV-1 Tat hijacks the human superelongation complex (SEC) to promote proviral transcription. Here we report the 5.9 A° 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.

Original language	English
Article number	e15910
Journal	eLife
Volume	5
Issue number	OCTOBER2016
DOIs	https://doi.org/10.7554/eLife.15910
State	Published - 12 Oct 2016
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Neuroscience
General Biochemistry,Genetics and Molecular Biology
General Immunology and Microbiology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.15910

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@article{0413548d04034155b10d85ac077ccd90,

title = "Insights into HIV-1 proviral transcription from integrative structure and dynamics of the tat:AFF4:P-TEFB:TAR complex",

abstract = "HIV-1 Tat hijacks the human superelongation complex (SEC) to promote proviral transcription. Here we report the 5.9 A° 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.",

author = "Ursula Schulze-Gahmen and Ignacia Echeverria and Goran Stjepanovic and Yun Bai and Huasong Lu and Dina Schneidman-Duhovny and Doudna, \{Jennifer A.\} and Qiang Zhou and Andrej Sali and Hurley, \{James H.\}",

note = "Publisher Copyright: {\textcopyright} Schulze-Gahmen et al.",

year = "2016",

month = oct,

day = "12",

doi = "10.7554/eLife.15910",

language = "الإنجليزيّة",

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T1 - Insights into HIV-1 proviral transcription from integrative structure and dynamics of the tat:AFF4:P-TEFB:TAR complex

AU - Schulze-Gahmen, Ursula

AU - Echeverria, Ignacia

AU - Stjepanovic, Goran

AU - Bai, Yun

AU - Lu, Huasong

AU - Schneidman-Duhovny, Dina

AU - Doudna, Jennifer A.

AU - Zhou, Qiang

AU - Sali, Andrej

AU - Hurley, James H.

PY - 2016/10/12

Y1 - 2016/10/12

N2 - HIV-1 Tat hijacks the human superelongation complex (SEC) to promote proviral transcription. Here we report the 5.9 A° 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.

AB - HIV-1 Tat hijacks the human superelongation complex (SEC) to promote proviral transcription. Here we report the 5.9 A° 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.

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U2 - 10.7554/eLife.15910

DO - 10.7554/eLife.15910

M3 - مقالة

C2 - 27731797

SN - 2050-084X

VL - 5

JO - eLife

JF - eLife

IS - OCTOBER2016

M1 - e15910

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

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