Thrombin inhibits the anti-myeloperoxidase and ferroxidase functions of ceruloplasmin: relevance in rheumatoid arthritis. / Sokolov, A.V.; Acquasaliente, L.; Kostevich, V.A.; Frasson, R.; Zakharova, E.T.; Pontarollo, G.; Vasilyev, V.B.; De Filippis, V.
In: Free Radical Biology and Medicine, Vol. 86, 2015, p. 279-294.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Thrombin inhibits the anti-myeloperoxidase and ferroxidase functions of ceruloplasmin: relevance in rheumatoid arthritis
AU - Sokolov, A.V.
AU - Acquasaliente, L.
AU - Kostevich, V.A.
AU - Frasson, R.
AU - Zakharova, E.T.
AU - Pontarollo, G.
AU - Vasilyev, V.B.
AU - De Filippis, V.
PY - 2015
Y1 - 2015
N2 - Human ceruloplasmin (CP) is a multifunctional copper-binding protein produced in the liver. CP oxidizes Fe2+ to Fe3+, decreasing the concentration of Fe2+ available for generating harmful oxidant species. CP is also a potent inhibitor of leukocyte myeloperoxidase (MPO) (Kd=130nM), a major source of oxidants in vivo. Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting flexible joints and characterized by activation of both inflammatory and coagulation processes. Indeed, the levels of CP, MPO, and thrombin are markedly increased in the synovial fluid of RA patients. Here we show that thrombin cleaves CP in vitro at 481Arg-Ser482 and 887Lys-Val888 bonds, generating a nicked species that retains the native-like fold and the ferroxidase activity of the intact protein, whereas the MPO inhibitory function of CP is abrogated. Analysis of the synovial fluid of 24 RA patients reveals that CP is proteolytically degraded to a variable extent, with a fragmentation pattern similar to that observed wit
AB - Human ceruloplasmin (CP) is a multifunctional copper-binding protein produced in the liver. CP oxidizes Fe2+ to Fe3+, decreasing the concentration of Fe2+ available for generating harmful oxidant species. CP is also a potent inhibitor of leukocyte myeloperoxidase (MPO) (Kd=130nM), a major source of oxidants in vivo. Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting flexible joints and characterized by activation of both inflammatory and coagulation processes. Indeed, the levels of CP, MPO, and thrombin are markedly increased in the synovial fluid of RA patients. Here we show that thrombin cleaves CP in vitro at 481Arg-Ser482 and 887Lys-Val888 bonds, generating a nicked species that retains the native-like fold and the ferroxidase activity of the intact protein, whereas the MPO inhibitory function of CP is abrogated. Analysis of the synovial fluid of 24 RA patients reveals that CP is proteolytically degraded to a variable extent, with a fragmentation pattern similar to that observed wit
KW - Ceruloplasmin
KW - Myeloperoxidase
KW - Oxidants
KW - Protein–protein interaction
KW - Proteolysis
KW - Rheumatoid arthritis
KW - Surface plasmon resonance
KW - Thrombin
U2 - 10.1016/j.freeradbiomed.2015.05.016
DO - 10.1016/j.freeradbiomed.2015.05.016
M3 - Article
VL - 86
SP - 279
EP - 294
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
ER -
ID: 3938943