Protein arginine deiminase 2 binds calcium in an ordered fashion: Implications for inhibitor design
Abstract
Protein arginine deiminases (PADs) are calcium-dependent histone-modifying enzymes whose activity is dysregulated in inflammatory diseases and cancer. PAD2 functions as an Estrogen Receptor (ER) coactivator in breast cancer cells via the citrullination of histone tail arginine residues at ER binding sites. Although an attractive therapeutic target, the mechanisms that regulate PAD2 activity are largely unknown, especially the detailed role of how calcium facilitates enzyme activation. To gain insights into these regulatory processes, we determined the first structures of PAD2 (27 in total), and through calcium-titrations by X-ray crystallography, determined the order of binding and affinity for the six calcium ions that bind and activate this enzyme. These structures also identified several PAD2 regulatory elements, including a calcium switch that controls proper positioning of the catalytic cysteine residue, and a novel active site shielding mechanism. Additional biochemical and mass-spectrometry-based hydrogen/deuterium exchange studies support these structural findings. The identification of multiple intermediate calcium-bound structures along the PAD2 activation pathway provides critical insights that will aid the development of allosteric inhibitors targeting the PADs.
- Authors:
-
- The Scripps Research Institute, Jupiter, FL (United States); Virginia Polytechnic Institute and State Univ., Blacksburg, VA (United States)
- The Scripps Research Institute, Jupiter, FL (United States)
- The Scripps Research Institute, Jupiter, FL (United States); Univ. of Massachusetts Medical School, Worcester, MA (United States)
- Washington Univ. in St. Louis, St. Louis, MO (United States)
- GlaxoSmithKline (United Kingdom). Medicines Research Centre.
- Cornell Univ., Ithaca, NY (United States)
- Publication Date:
- Research Org.:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1215427
- Alternate Identifier(s):
- OSTI ID: 1215445
- Grant/Contract Number:
- W871XWH-07-0372; GM079357; GM103422; AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- ACS Chemical Biology
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 4; Journal ID: ISSN 1554-8929
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Slade, Daniel J., Fang, Pengfei, Dreyton, Christina J., Zhang, Ying, Fuhrmann, Jakob, Rempel, Don, Bax, Benjamin D., Coonrod, Scott A., Lewis, Huw D., Guo, Min, Gross, Michael L., and Thompson, Paul R. Protein arginine deiminase 2 binds calcium in an ordered fashion: Implications for inhibitor design. United States: N. p., 2015.
Web. doi:10.1021/cb500933j.
Slade, Daniel J., Fang, Pengfei, Dreyton, Christina J., Zhang, Ying, Fuhrmann, Jakob, Rempel, Don, Bax, Benjamin D., Coonrod, Scott A., Lewis, Huw D., Guo, Min, Gross, Michael L., & Thompson, Paul R. Protein arginine deiminase 2 binds calcium in an ordered fashion: Implications for inhibitor design. United States. https://doi.org/10.1021/cb500933j
Slade, Daniel J., Fang, Pengfei, Dreyton, Christina J., Zhang, Ying, Fuhrmann, Jakob, Rempel, Don, Bax, Benjamin D., Coonrod, Scott A., Lewis, Huw D., Guo, Min, Gross, Michael L., and Thompson, Paul R. Mon .
"Protein arginine deiminase 2 binds calcium in an ordered fashion: Implications for inhibitor design". United States. https://doi.org/10.1021/cb500933j. https://www.osti.gov/servlets/purl/1215427.
@article{osti_1215427,
title = {Protein arginine deiminase 2 binds calcium in an ordered fashion: Implications for inhibitor design},
author = {Slade, Daniel J. and Fang, Pengfei and Dreyton, Christina J. and Zhang, Ying and Fuhrmann, Jakob and Rempel, Don and Bax, Benjamin D. and Coonrod, Scott A. and Lewis, Huw D. and Guo, Min and Gross, Michael L. and Thompson, Paul R.},
abstractNote = {Protein arginine deiminases (PADs) are calcium-dependent histone-modifying enzymes whose activity is dysregulated in inflammatory diseases and cancer. PAD2 functions as an Estrogen Receptor (ER) coactivator in breast cancer cells via the citrullination of histone tail arginine residues at ER binding sites. Although an attractive therapeutic target, the mechanisms that regulate PAD2 activity are largely unknown, especially the detailed role of how calcium facilitates enzyme activation. To gain insights into these regulatory processes, we determined the first structures of PAD2 (27 in total), and through calcium-titrations by X-ray crystallography, determined the order of binding and affinity for the six calcium ions that bind and activate this enzyme. These structures also identified several PAD2 regulatory elements, including a calcium switch that controls proper positioning of the catalytic cysteine residue, and a novel active site shielding mechanism. Additional biochemical and mass-spectrometry-based hydrogen/deuterium exchange studies support these structural findings. The identification of multiple intermediate calcium-bound structures along the PAD2 activation pathway provides critical insights that will aid the development of allosteric inhibitors targeting the PADs.},
doi = {10.1021/cb500933j},
journal = {ACS Chemical Biology},
number = 4,
volume = 10,
place = {United States},
year = {Mon Jan 26 00:00:00 EST 2015},
month = {Mon Jan 26 00:00:00 EST 2015}
}
Web of Science
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