Chemical Tools To Decipher Regulation of Phosphatases by Proline Isomerization on Eukaryotic RNA Polymerase II

Mayfield, Joshua E.; Fan, Shuang; Wei, Shuo; Zhang, Mengmeng; Li, Bing; Ellington, Andrew D.; Etzkorn, Felicia A.; Zhang, Yan Jessie

doi:10.1021/acschembio.5b00296

Chemical Tools To Decipher Regulation of Phosphatases by Proline Isomerization on Eukaryotic RNA Polymerase II

Journal Article · Wed Sep 02 00:00:00 EDT 2015 · ACS Chemical Biology

DOI:https://doi.org/10.1021/acschembio.5b00296· OSTI ID:1252772

Mayfield, Joshua E. ^[1]; Fan, Shuang ^[2]; Wei, Shuo ^[3]; Zhang, Mengmeng ^[1]; Li, Bing ^[4]; Ellington, Andrew D. ^[1]; Etzkorn, Felicia A. ^[2]; Zhang, Yan Jessie ^[1]

Univ. of Texas, Austin, TX (United States)
Virginia Polytechnic Inst. and State Univ. (Virginia Tech), Blacksburg, VA (United States)
Harvard Medical School, Boston, MA (United States)
UT Southwestern Medical Center, Dallas, TX (United States)

Proline isomerization greatly impacts biological signaling but is subtle and difficult to detect in proteins. We characterize this poorly understood regulatory mechanism for RNA polymerase II carboxyl terminal domain (CTD) phosphorylation state using novel, direct, and quantitative chemical tools. We determine the proline isomeric preference of three CTD phosphatases: Ssu72 as cis-proline specific, Scp1 and Fcp1 as strongly trans-preferred. Due to this inherent characteristic, these phosphatases respond differently to enzymes that catalyze the isomerization of proline, like Ess1/Pin1. We demonstrate that this selective regulation of RNA polymerase II phosphorylation state exists within human cells, consistent with in vitro assays. These results support a model in which, instead of a global enhancement of downstream enzymatic activities, proline isomerases selectively boost the activity of a subset of CTD regulatory factors specific for cis-proline. This leads to diversified phosphorylation states of CTD in vitro and in cells. In conclusion, we provide the chemical tools to investigate proline isomerization and its ability to selectively enhance signaling in transcription and other biological contexts.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; USDOE; Welch Foundation

OSTI ID:: 1252772

Journal Information:: ACS Chemical Biology, Journal Name: ACS Chemical Biology Journal Issue: 10 Vol. 10; ISSN 1554-8929

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Novel polysaccharide binding to the N-terminal tail of galectin-3 is likely modulated by proline isomerization Miller, Michelle C.; Zheng, Y.; Yan, Jingmin Glycobiology, Vol. 27, Issue 11 https://doi.org/10.1093/glycob/cwx071	journal	September 2017
The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target Zhou, Xiao Zhen; Lu, Kun Ping Nature Reviews Cancer, Vol. 16, Issue 7 https://doi.org/10.1038/nrc.2016.49	journal	June 2016
Structural determinants for accurate dephosphorylation of RNA polymerase II by its cognate C-terminal domain (CTD) phosphatase during eukaryotic transcription Irani, Seema; Sipe, Sarah N.; Yang, Wanjie Journal of Biological Chemistry, Vol. 294, Issue 21 https://doi.org/10.1074/jbc.ra119.007697	journal	April 2019

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Chemical Tools To Decipher Regulation of Phosphatases by Proline Isomerization on Eukaryotic RNA Polymerase II

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