TY - JOUR

T1 - Interaction of macrophage migration inhibitory factor with ceruloplasmin: role of labile copper ions

AU - Kostevich, V.A.

AU - Sokolov, A.V.

AU - Grudinina, N.A.

AU - Zakharova, E.T.

AU - Samygina, V.R.

AU - Vasilyev, V.B.

PY - 2015

Y1 - 2015

N2 - Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is a target for pharmacological treatment of sepsis and malignant tumors. Inhibition of tautomerase activity of MIF in reaction with p-hydroxyphenylpyruvate (HPP) was observed in the presence of ceruloplasmin (CP), a copper-containing plasma protein. Binding labile copper ions to CP (CP+Cu(II)) is a prerequisite for MIF inhibiting. CP+Cu(II) is shown to be an uncompetitive inhibitor of MIF (Ki ~ 37 nM), which suggests formation of a complex ‘MIF-HPP-CP-Cu(II)’. Filtration of CP+Cu(II) on a column with Chelex-100, otherwise the presence of high concentrations of histidine, cysteine or methionine abrogated the inhibitory effect of CP. Adding salts of Co(II) and Ni(II) that replace copper ions in the labile sites prevented the inhibitory effect of CP+Cu(II). Limited proteolysis of CP by thrombin diminished its oxidase activity in reaction with p-phenylenediamine, but endowed it with the capacity of inhibiting MIF. Covalent modification of

AB - Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, is a target for pharmacological treatment of sepsis and malignant tumors. Inhibition of tautomerase activity of MIF in reaction with p-hydroxyphenylpyruvate (HPP) was observed in the presence of ceruloplasmin (CP), a copper-containing plasma protein. Binding labile copper ions to CP (CP+Cu(II)) is a prerequisite for MIF inhibiting. CP+Cu(II) is shown to be an uncompetitive inhibitor of MIF (Ki ~ 37 nM), which suggests formation of a complex ‘MIF-HPP-CP-Cu(II)’. Filtration of CP+Cu(II) on a column with Chelex-100, otherwise the presence of high concentrations of histidine, cysteine or methionine abrogated the inhibitory effect of CP. Adding salts of Co(II) and Ni(II) that replace copper ions in the labile sites prevented the inhibitory effect of CP+Cu(II). Limited proteolysis of CP by thrombin diminished its oxidase activity in reaction with p-phenylenediamine, but endowed it with the capacity of inhibiting MIF. Covalent modification of

KW - Ceruloplasmin

KW - Macrophage migration inhibitory factor

KW - Protein–protein interaction

KW - Tautomerase activity

KW - p-Hydroxyphenylpyruvate

U2 - 10.1007/s10534-015-9868-2

DO - 10.1007/s10534-015-9868-2

M3 - Article

VL - 28

SP - 817

EP - 826

JO - BioMetals

JF - BioMetals

SN - 0966-0844

IS - 5

ER -