Sandbox Reserved 1096: Difference between revisions

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Two main types of Arginine Deiminases are extensively expressed in the [https://en.wikipedia.org/wiki/Central_nervous_system Central Nervous System (CNS)]:PAD2 and PAD4<ref name="ARTMS"/>. PAD2, mainly produced by oligodendrocytes was found to be implicated in pathological citrullination of [https://en.wikipedia.org/wiki/Myelin_basic_protein Myelin Basic Protein (MBP)]. MBP along with oligodendrocyte glycoprotein (MOG) and proteolipid protein (PLP) play an essential role in [https://en.wikipedia.org/wiki/Myelin myelin sheath] stabilization by maintaining adequate compaction and adhesion between axonal cytoplasmic surfaces and negatively charged lipids of [https://en.wikipedia.org/wiki/Myelin myelin sheath]. [https://en.wikipedia.org/wiki/Citrullination Citrullination] of MBP is thought to be a naturally occuring post-translational modification of the immature CNS<ref name="ARTMS" /><ref>PMID: 7518827</ref>, 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)<ref>PMID: 7518827</ref><ref>PMID: 8687186</ref>. 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<ref name="ARTMS" />. 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 <ref>PMID: 22420465</ref>. These modifications may naturally occur as regulatory processes in cells but, in the case of MBP's citrullination, they may promote/initiate pathological states<ref name="ARTMS" />. 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 [https://en.wikipedia.org/wiki/Neoepitope neo-epitopes] for which no tolerance exists; 2) Citrullination may induce MBP's misfolding exposing [https://en.wikipedia.org/wiki/Immunodominance immunodominant] [https://en.wikipedia.org/wiki/Epitope epitopes]<ref name="ARTMS"/>. 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<ref>PMID: 12898292</ref>. These newly generated versions of MBP enhance the exposure of a central-membrane-binding fragment that represents a primary immunodominant epitope in the [https://en.wikipedia.org/wiki/Cytoplasm cytoplasm] and is thus its [https://en.wikipedia.org/wiki/Proteolysis proteolysis] is capable of generating more immunodominant species that trigger immunological responses<ref>PMID:16537438</ref><ref>PMID: 17531841</ref>. 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 [https://en.wikipedia.org/wiki/Estrogen_receptor Estrogen Receptor] (ER) coactivator in [https://en.wikipedia.org/wiki/Breast_cancer Breast cancer] cells, using the citrullination of histone tail arginine residues at ER binding sites. This makes it an attractive therapeutic target, yet, the mechanisms that regulates it are for a major part unknown. Indeed, it is used as a component of ER-related gene expression that is positively correlated with [https://proteopedia.org/wiki/index.php/Herceptin_-_Mechanism_of_Action HER2] protein levels in breast cancer cell lines, and in primary HER2+ breast tumors. This shows that PAD2 activity plays a role in breast cancer progression. The inhibition of PAD2 decreases ER target-gene expression. Moreover, when in presence of CL-amidine, which is PAD inhibitor, the tumor burden in a breast cancer.

==Publication Abstract from ACS Publications <ref name="ART1" />==

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 Two main types of Arginine Deiminases are extensively expressed in the [https://en.wikipedia.org/wiki/Central_nervous_system Central Nervous System (CNS)]:PAD2 and PAD4<ref name="ARTMS"/>. PAD2, mainly produced by oligodendrocytes was found to be implicated in pathological citrullination of [https://en.wikipedia.org/wiki/Myelin_basic_protein Myelin Basic Protein (MBP)]. MBP along with oligodendrocyte glycoprotein (MOG) and proteolipid protein (PLP) play an essential role in [https://en.wikipedia.org/wiki/Myelin myelin sheath] stabilization by maintaining adequate compaction and adhesion between axonal cytoplasmic surfaces and negatively charged lipids of [https://en.wikipedia.org/wiki/Myelin myelin sheath]. [https://en.wikipedia.org/wiki/Citrullination Citrullination] of MBP is thought to be a naturally occuring post-translational modification of the immature CNS<ref name="ARTMS" /><ref>PMID: 7518827</ref>, 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)<ref>PMID: 7518827</ref><ref>PMID: 8687186</ref>. 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<ref name="ARTMS" />. 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 <ref>PMID: 22420465</ref>. These modifications may naturally occur as regulatory processes in cells but, in the case of MBP's citrullination, they may promote/initiate pathological states<ref name="ARTMS" />. 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 [https://en.wikipedia.org/wiki/Neoepitope neo-epitopes] for which no tolerance exists; 2) Citrullination may induce MBP's misfolding exposing [https://en.wikipedia.org/wiki/Immunodominance immunodominant] [https://en.wikipedia.org/wiki/Epitope epitopes]<ref name="ARTMS"/>. 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<ref>PMID: 12898292</ref>. These newly generated versions of MBP enhance the exposure of a central-membrane-binding fragment that represents a primary immunodominant epitope in the [https://en.wikipedia.org/wiki/Cytoplasm cytoplasm] and is thus its [https://en.wikipedia.org/wiki/Proteolysis proteolysis] is capable of generating more immunodominant species that trigger immunological responses<ref>PMID:16537438</ref><ref>PMID: 17531841</ref>. 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 [https://en.wikipedia.org/wiki/Estrogen_receptor Estrogen Receptor] (ER) coactivator in [https://en.wikipedia.org/wiki/Breast_cancer Breast cancer] cells, using the citrullination of histone tail arginine residues at ER binding sites. This makes it an attractive therapeutic target, yet, the mechanisms that regulates it are for a major part unknown. Indeed, it is used as a component of ER-related gene expression that is positively correlated with [https://proteopedia.org/wiki/index.php/Herceptin_-_Mechanism_of_Action HER2] protein levels in breast cancer cell lines, and in primary HER2+ breast tumors. This shows that PAD2 activity plays a role in breast cancer progression. The inhibition of PAD2 decreases ER target-gene expression. Moreover, when in presence of CL-amidine, which is PAD inhibitor, the tumor burden in a breast cancer.
 ==Publication Abstract from ACS Publications <ref name="ART1" />==