Phosphorylation induces sequence-specific conformational switches in the RNA polymerase II C-terminal domain

Nature Communications
Eric B GibbsScott A Showalter

Abstract

The carboxy-terminal domain (CTD) of the RNA polymerase II (Pol II) large subunit cycles through phosphorylation states that correlate with progression through the transcription cycle and regulate nascent mRNA processing. Structural analyses of yeast and mammalian CTD are hampered by their repetitive sequences. Here we identify a region of the Drosophila melanogaster CTD that is essential for Pol II function in vivo and capitalize on natural sequence variations within it to facilitate structural analysis. Mass spectrometry and NMR spectroscopy reveal that hyper-Ser5 phosphorylation transforms the local structure of this region via proline isomerization. The sequence context of this switch tunes the activity of the phosphatase Ssu72, leading to the preferential de-phosphorylation of specific heptads. Together, context-dependent conformational switches and biased dephosphorylation suggest a mechanism for the selective recruitment of cis-proline-specific regulatory factors and region-specific modulation of the CTD code that may augment gene regulation in developmentally complex organisms.

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Citations

May 16, 2017·Archives of Biochemistry and Biophysics·Eric B GibbsScott A Showalter
Oct 27, 2017·Proceedings of the National Academy of Sciences of the United States of America·Olga JasnovidovaRichard Stefl
Jan 19, 2018·Annual Review of Biophysics·Alex S Holehouse, Rohit V Pappu
May 24, 2018·Chembiochem : a European Journal of Chemical Biology·Maria Grazia MurraliRoberta Pierattelli
Sep 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Min-Hyung ChoVincent J Hilser
Aug 22, 2018·Nature Communications·Franziska ZoselBenjamin Schuler
Aug 22, 2018·Nature Structural & Molecular Biology·Marc BoehningMarkus Zweckstetter
Mar 17, 2019·International Journal of Molecular Sciences·Philipp Selenko
Sep 2, 2020·International Journal of Molecular Sciences·Greta BianchiStefania Brocca
Oct 21, 2020·Emerging Topics in Life Sciences·Erik W Martin, Alex S Holehouse
Mar 8, 2020·Archives of Biochemistry and Biophysics·Andrea Soranno
Mar 25, 2019·Methods : a Companion to Methods in Enzymology·Katlyn Hughes Burriss, Amber L Mosley
Oct 11, 2017·Biophysical Journal·Eric B GibbsScott A Showalter
Mar 8, 2021·Journal of Molecular Biology·Mukesh Kumar Venkat RamaniYan Zhang
May 16, 2018·Journal of Molecular Biology·Anuradha MittalRohit V Pappu
Jun 17, 2020·Molecular Cell·Porfirio Quintero-CadenaPaul W Sternberg
Oct 20, 2019·Current Opinion in Structural Biology·Aaron H Phillips, Richard W Kriwacki
May 1, 2021·International Journal of Molecular Sciences·Soeun HwangChang-Woo Lee
May 13, 2021·Scientific Reports·Sonia T NicolaouJim Warwicker
Jul 9, 2021·Current Research in Structural Biology·Juliane F RipkaLaura S Itzhaki
Dec 12, 2018·The Journal of Physical Chemistry. B·Erik C CookScott A Showalter
Oct 1, 2021·Biophysical Journal·Emery T UsherScott A Showalter
May 19, 2021·Cold Spring Harbor Perspectives in Biology·Feiyue Lu, Timothée Lionnet

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Methods Mentioned

BETA
NMR
transgenic
X-ray
chemical exchange
electrophoresis
size exclusion chromatography
gel filtration

Software Mentioned

Primus qt
Mnova
NMRPipe
Scaffold PTM
Topspin
BioXtas
δ2D
MATLAB
Sparky
Proteome

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