Sandbox Reserved 1096
From Proteopedia
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==General Description== | ==General Description== | ||
| + | <Structure load='4N20' size='450' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | ||
| + | '''''Protein Arginine Deiminase''''' type 2 also known as '''''PAD2''''' | ||
==Structural Features== | ==Structural Features== | ||
Revision as of 17:08, 9 January 2020
| This Sandbox is Reserved from 25/11/2019, through 30/9/2020 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1091 through Sandbox Reserved 1115. |
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Contents |
Human Arginine Deiminase Type 2
General Description
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Protein Arginine Deiminase type 2 also known as PAD2
Structural Features
Primary, secondary and tertiary structure
Calcium binding sites and active site
Catalysis of deimination
Citrullination of Arginine residues
Role in Human Health
Citrullination of Myelin Basic Protein (MBP) and Multiple Sclerosis
PAD2 and ER Target-gene Expression in Breast Cancer
Publication Abstract from PubMed
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.
