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' /> | <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''''', is a calcium-dependent [https://en.wikipedia.org/wiki/Enzyme enzyme] that catalyzes in humans the conversion of [https://en.wikipedia.org/wiki/Arginine Arginine] residues into [https://en.wikipedia.org/wiki/Citrulline Citrulline] in a [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modification] referred to as [https://en.wikipedia.org/wiki/Citrullination Citrullination]. The structure of '''''PAD2 Apoenzyme''''' described here was elucidated at a calcium concentration of 0mM (Ca2+) with a resolution of 1.657 Å by [https://en.wikipedia.org/wiki/X-ray_crystallography x-ray diffraction cristallography]<ref name="PDB">[https://www.rcsb.org/structure/4N20</ref> . The biological assembly of PAD2 consists of a head-to-tail dimer with immunoglobin-like domains and a nucleophilic [https://en.wikipedia.org/wiki/Cysteine cysteine] residue responsible of catalytic activity in the active site <ref>DOI:10.1021/cb500933j</ref>. | + | '''''Protein Arginine Deiminase type 2 ''''' also known as '''''PAD2''''', is a calcium-dependent [https://en.wikipedia.org/wiki/Enzyme enzyme] that catalyzes in humans the conversion of [https://en.wikipedia.org/wiki/Arginine Arginine] residues into [https://en.wikipedia.org/wiki/Citrulline Citrulline] in a [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modification] referred to as [https://en.wikipedia.org/wiki/Citrullination Citrullination]. The structure of '''''PAD2 Apoenzyme''''' described here was elucidated at a calcium concentration of 0mM (Ca2+) with a resolution of 1.657 Å by [https://en.wikipedia.org/wiki/X-ray_crystallography x-ray diffraction cristallography]<ref name="PDB">[https://www.rcsb.org/structure/4N20</ref> . The biological assembly of PAD2 consists of a head-to-tail dimer with immunoglobin-like domains and a nucleophilic [https://en.wikipedia.org/wiki/Cysteine cysteine] residue responsible of catalytic activity in the active site <ref name="ART1">DOI:10.1021/cb500933j</ref>. |
==Structural Features== | ==Structural Features== | ||
==='''Primary, secondary and tertiary structure'''=== | ==='''Primary, secondary and tertiary structure'''=== | ||
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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, is a calcium-dependent enzyme that catalyzes in humans the conversion of Arginine residues into Citrulline in a post-translational modification referred to as Citrullination. The structure of PAD2 Apoenzyme described here was elucidated at a calcium concentration of 0mM (Ca2+) with a resolution of 1.657 Å by x-ray diffraction cristallography[1] . The biological assembly of PAD2 consists of a head-to-tail dimer with immunoglobin-like domains and a nucleophilic cysteine residue responsible of catalytic activity in the active site [2].
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.
References
- ↑ [https://www.rcsb.org/structure/4N20
- ↑ Slade DJ, Fang P, Dreyton CJ, Zhang Y, Fuhrmann J, Rempel D, Bax BD, Coonrod SA, Lewis HD, Guo M, Gross ML, Thompson PR. Protein Arginine Deiminase 2 Binds Calcium in an Ordered Fashion: Implications for Inhibitor Design. ACS Chem Biol. 2015 Jan 26. PMID:25621824 doi:http://dx.doi.org/10.1021/cb500933j
