TY - JOUR
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.
N1 - Publisher Copyright:
© Schulze-Gahmen et al.
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.
UR - http://www.scopus.com/inward/record.url?scp=84992018153&partnerID=8YFLogxK
U2 - 10.7554/eLife.15910
DO - 10.7554/eLife.15910
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C2 - 27731797
AN - SCOPUS:84992018153
SN - 2050-084X
VL - 5
JO - eLife
JF - eLife
IS - OCTOBER2016
M1 - e15910
ER -
