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Loos, T, Mortier, A, Gouwy, M, Ronsse, I, Put, W, Lenaerts, JP, Van Damme, J and Proost, P (2008) Citrullination of CXCL10 and CXCL11 by peptidylarginine deiminase: a naturally occurring posttranslational modification of chemokines and new dimension of immunoregulation. Blood 112:2648-56
Interactions between chemokines and enzymes are vital in immunoregulation. Structural protein citrullination by peptidylarginine deiminase (PAD) has been associated with autoimmunity. In this report, we identified a novel naturally occurring posttranslational modification of chemokines, that is, the deimination of arginine at position 5 into citrulline of CXC chemokine ligand 10 (CXCL10) by rabbit PAD and human PAD2. Citrullination reduced (>/= 10-fold) the chemoattracting and signaling capacity of CXCL10 for CXC chemokine receptor 3 (CXCR3) transfectants; however, it did not affect CXCR3 binding. On T lymphocytes, though, citrullinated CXCL10 remained active but was again weaker than authentic CXCL10. PAD was also able to convert CXCL11, causing an impairment of CXCR3 signaling and T-cell activation, though less pronounced than for CXCL10. Similarly, receptor binding properties of CXCL11 were not altered by citrullination. However, deimination decreased heparin binding properties of both CXCL10 and CXCL11. Overall, chemokines are the first immune modulators reported of being functionally modified by citrullination. These data provide new structure-function dimensions for chemokines in leukocyte mobilization, disclosing an anti-inflammatory role for PAD. Additionally because citrullination has severe consequences for chemokine biology, this invites to reassess the involvement and impact of PAD and citrullinated peptides in inflammation, autoimmunity, and hematologic disorders.
Amino Acid Sequence; Animals; Cell Line; Chemokine CXCL10/chemistry; Chemokine CXCL10/immunology; Chemokine CXCL10/isolation & purification; Chemokine CXCL10/pharmacology; Chemokine CXCL11/immunology; Chemokine CXCL11/pharmacology; Citrulline/metabolism; Glycosaminoglycans/metabolism; Heparin/metabolism; Humans; Hydrolases/metabolism; Lymphocyte Activation/drug effects; Molecular Sequence Data; Phytohemagglutinins/pharmacology; Protein Binding/drug effects; Protein Isoforms/metabolism; Protein Processing, Post-Translational/drug effects; Rabbits; Receptors, CXCR/metabolism; Receptors, CXCR3/metabolism; T-Lymphocytes/cytology; T-Lymphocytes/drug effects; Transfection