Sandbox Reserved 1096

From Proteopedia

Revision as of 10:58, 12 January 2020 by Luis Alejandro Cano (Talk | contribs)
Jump to: navigation, search
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.
To get started:
  • Click the edit this page tab at the top. Save the page after each step, then edit it again.
  • show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page.
  • Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc.

More help: Help:Editing

Contents

Human Peptidylarginine Deiminase Type 2

General Description

Insert caption here

Drag the structure with the mouse to rotate

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]. In humans, five genes clustered in a single locus code for Arginine deiminases: PADI1,PADI2,PADI3,PADI4,PADI6[3]. Expression of different isoforms of PAD seem to depend strongly on cell types and tissues even though PAD2 may be an ubiquist protein [3]. Peptidyl Arginine Deiminase type 2 appears to have an essential role in the development of Breast Cancer [2], Multiple Sclerosis(MS)[4] and other degenerative disorders such as Rheumatoid Arthritis [3] thus making it a potential target for inhibitor design treatments. Related structures for PAD2 include: 4n2b and 4n2c.

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

Two main types of Arginine Deiminases are extensively expressed in the Central Nervous System (CNS):PAD2 and PAD4[4]. PAD2, mainly produced by oligodendrocytes was found to be implicated in pathological citrullination of Myelin Basic Protein (MBP). MBP along with oligodendrocyte glycoprotein (MOG) and proteolipid protein (PLP) play an essential role in myelin sheath stabilization by maintaining adequate compaction and adhesion between axonal cytoplasmic surfaces and negatively charged lipids of myelin sheath. Citrullination of MBP is thought to be a naturally occuring post-translational modification of the immature CNS[5][4], for instance around 20% of isolated MBP is citrullinated in normal human adults whereas an average of 45% citrullinated MBP was detected in chronic MS patients and up to 80% for fulminating MS (Marburg's Syndrome)[6][7]. Considering hyper-citrullination of MBP marks important stages in the development of the CNS, MBP's citrullination by PAD2 in MS patients suggests either a switch to immaturity as a repair mechanism for neurological damage[4].

PAD2 and ER Target-gene Expression in Breast Cancer

Publication Abstract from ACS Publications [2]

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

  1. ↑ [https://www.rcsb.org/structure/4N20
  2. ↑ 2.0 2.1 2.2 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
  3. ↑ 3.0 3.1 3.2 Mechin MC, Nachat R, Coudane F, Adoue V, Arnaud J, Serre G, Simon M. [Deimination or citrullination, a post-translational modification with many physiological and pathophysiological facets]. Med Sci (Paris). 2011 Jan;27(1):49-54. doi: 10.1051/medsci/201127149. PMID:21299962 doi:http://dx.doi.org/10.1051/medsci/201127149
  4. ↑ 4.0 4.1 4.2 4.3 Mechin MC, Nachat R, Coudane F, Adoue V, Arnaud J, Serre G, Simon M. [Deimination or citrullination, a post-translational modification with many physiological and pathophysiological facets]. Med Sci (Paris). 2011 Jan;27(1):49-54. doi: 10.1051/medsci/201127149. PMID:21299962 doi:http://dx.doi.org/10.1051/medsci/201127149
  5. ↑ Moscarello MA, Wood DD, Ackerley C, Boulias C. Myelin in multiple sclerosis is developmentally immature. J Clin Invest. 1994 Jul;94(1):146-54. doi: 10.1172/JCI117300. PMID:7518827 doi:http://dx.doi.org/10.1172/JCI117300
  6. ↑ Moscarello MA, Wood DD, Ackerley C, Boulias C. Myelin in multiple sclerosis is developmentally immature. J Clin Invest. 1994 Jul;94(1):146-54. doi: 10.1172/JCI117300. PMID:7518827 doi:http://dx.doi.org/10.1172/JCI117300
  7. ↑ Wood DD, Bilbao JM, O'Connors P, Moscarello MA. Acute multiple sclerosis (Marburg type) is associated with developmentally immature myelin basic protein. Ann Neurol. 1996 Jul;40(1):18-24. doi: 10.1002/ana.410400106. PMID:8687186 doi:http://dx.doi.org/10.1002/ana.410400106
Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1096"
Personal tools