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Human Peptidylarginine 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]. 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
The structure of the apoenzyme apoPAD2 shows a stable head to tail dimer.The monomer is formed by 2 immunoglobulin-like domains and a C-term catalytic domain calcium binding site. There are six different calcium binding sites C1 to C6 C2-5 are unoccupied in apoPAD2 but there is an electron density on C1 and C6 so those are occupied by calcium[5], 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]. Given that hyper-citrullination of MBP marks important stages in the development of the CNS, MBP's citrullination by PAD2 in MS patients suggests a switch to immaturity as a repair mechanism for neurological damage[4]. This switch to immaturity could however promote or initiate pathological effects in MS.
Numerous post-translational modifications in myelin sheath-related proteins can alter folding and 3D configuration of polypeptides thus modifying functional and structural properties of the tissue [8]. These modifications may naturally occur as regulatory processes in cells but, in the case of MBP's citrullination, they may promote/initiate pathological states[4]. Two main consequences regarding Myelin Basic Protein citrullinaton have been proposed: 1) Change of arginine residues to citrulline by PADs could trigger the generation of neo-epitopes for which no tolerance exists; 2) Citrullination may induce MBP's misfolding exposing immunodominant epitopes[4]. Both effects result in auto-immune responses towards CNS tissues in the first case due to the newly generated neo-epitopes that trigger 'new' immunological responses. In the second case, pertubation of internal electrostatic interations within MBP as a consequence of citrullination may generate misfolded versions of the protein in the myelin sheath that were proven to be more extended[9]. These newly generated versions of MBP enhance the exposure of a central-membrane-binding fragment that represents a primary immunodominant epitope in the cytoplasm and is thus its proteolysis is capable of generating more immunodominant species that trigger immunological responses[10][11]. Modification of MBP's functional properties may have a direct impact in adhesion and compaction of the myelin sheath promoting demyelination in Multiple Sclerosis. Related structures of immunological associations with Myelin Basic Protein have been studied in: 1k2d and 1bx2.
PAD2 and ER Target-gene Expression in Breast Cancer
PAD2 functions as an Estrogen Receptor (ER) coactivator in Breast cancer cells, using the citrullination of histone tail arginine residues at ER binding sites.[12]