Caught red handed: modeling and confirmation of the myeloperoxidase ceruloplasmin alpha-thrombin complex

Zabrodskaya, Yana A.; Егоров, Владимир В.; Соколов, А. В.; Швецов, А. В.; Gorshkova, Yu. E.; Ivankov, Oleksandr I.; Kostevich, Valeria A.; Горбунов, Н. П.; Ramsay, Edward; Fedorova, Natalia D.; Bondarenko, A. B.; Vasilyev, V. B.

doi:10.1007/s10534-022-00432-2

Cited by 4 publications

(3 citation statements)

References 30 publications

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“…It is to be noted that binding with MPO did not result in the inhibition of enzyme activity for all forms of ceruloplasmin. Breaking of one bond in the polypeptide chain could be enough for the loss of inhibitory potential of ceruloplasmin towards MPO even though the efficacy of its binding with MPO was not influenced [ 32 ]. Considering that about half of HSA-MG protein is capable of binding with MPO ( Figure 3 ), it is not apparent that all subsets of modified albumin inhibit activity of MPO with the same efficacy.…”

Section: Discussionmentioning

confidence: 99%

Methylglyoxal-Modified Human Serum Albumin Binds to Leukocyte Myeloperoxidase and Inhibits its Enzymatic Activity

et al. 2022

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Hyperglycemia in diabetes mellitus induces modification of proteins by glucose and its derivative methylglyoxal (MG). Neutrophils perform their bactericidal activity mainly via reactive halogen (RHS) and oxygen (ROS) species generation catalyzed by myeloperoxidase (MPO) stored in neutrophil azurophilic granules (AGs) and membrane NADPH oxidase, respectively. Herein, we study the binding of human serum albumin (HSA) modified with MG (HSA-MG) to MPO and its effects on MPO activity and release by neutrophils. Peroxidase activity of MPO was registered by oxidation of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, and chlorinating activity by decolorization of Celestine blue B dye. Binding of HSA-MG to MPO was studied by affinity chromatography, disc-electrophoresis, ligand Western blotting and enzyme-linked solid phase immunoassay using monoclonal antibodies (mAbs) to MPO. ROS and RHS generation were detected by lucigenin (Luc) and luminol (Lum) chemiluminescence (CL), respectively. Neutrophil degranulation was assessed by flow cytometry using fluorescent labeled antibodies to the marker proteins CD63 from AGs and CD11b from peroxidase-negative granules (PNGs). NETosis was assayed by quantifying DNA network-like structures (NET-like structures) in blood smears stained by Romanowsky. HSA-MG bound to MPO, giving a stable complex (Kd = 1.5 nM) and competing with mAbs, and non-competitively inhibited peroxidase and chlorinating MPO activity and induced degranulation of PNGs but not of AGs. HSA-MG enhanced Luc-CL per se or following PMA, unlike Lum-CL, and did not affect spontaneous or PMA-stimulated NETosis. Thus, HSA modified under hyperglycemia-like conditions stimulated NADPH oxidase of neutrophils but dampened their functions dependent on activity of MPO, with no effect on its release via degranulation or NETosis. This phenomenon could underlie the downregulation of bactericidal activity of MPO and neutrophils, and hence of innate immunity, giving rise to wound healing impairment and susceptibility to infection in patients with hyperglycemia.

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Section: Discussionmentioning

confidence: 99%

Methylglyoxal-Modified Human Serum Albumin Binds to Leukocyte Myeloperoxidase and Inhibits its Enzymatic Activity

et al. 2022

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“…The function P ( R ) = γ c ( R ) · R is evaluated, where γ c ( R ) is the characteristic function of thickness. The visualization of scattering objects based on SANS data was performed according to the ATSAS manual using DAMMIN [32] as was described earlier [33].…”

Section: Methodsmentioning

confidence: 99%

How the immune mousetrap works: structural evidence for the immunomodulatory action of a peptide from influenza NS1 protein

Zabrodskaya,

Tsvetkov,

Shurygina

et al. 2023

Preprint

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One of the critical stages of the T-cell immune response is the dimerization of the intramembrane domains of T-cell receptors (TCR). Structural similarities between the immunosuppressive domains of viral proteins and the transmembrane domains of TCR have led several authors to hypothesize the mechanism of immune response suppression by highly pathogenic viruses: viral proteins embed themselves in the membrane and act on the intramembrane domain of the TCRalpha subunit, hindering its functional oligomerization. It has also been suggested that this mechanism is used by influenza A virus in NS1-mediated immunosuppression. We have shown that the peptide corresponding to the primary structure of the potential immunosuppressive domain of NS1 protein (G51) can reduce concanavalin A-induced proliferation of PBMC cells, as well as in vitro, G51 can affect the oligomerization of the core peptide corresponding to the intramembrane domain of TCR, using AFM and small-angle neutron scattering.The results obtained usingin celluloandin vitromodel systems suggest the presence of functional interaction between the NS1 fragment and the intramembrane domain of the TCR alpha subunit. We have proposed a possible scheme for such interaction obtained by computer modeling.This suggests the existence of another NS1-mediated mechanism of immunosuppression in influenza.Abstract Figure

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“…(𝑅) is the characteristic function of thickness. The visualization of scattering objects based on SANS data was performed according to the ATSAS manual using DAMMIN [32] as was described earlier [33].…”

Section: Small-angle Neutron Scattering (Sans)mentioning

confidence: 99%

How the immune mousetrap works: Structural evidence for the immunomodulatory action of a peptide from influenza NS1 protein

Zabrodskaya,

Tsvetkov,

Shurygina

et al. 2024

Biophysical Chemistry

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Caught red handed: modeling and confirmation of the myeloperoxidase ceruloplasmin alpha-thrombin complex

Cited by 4 publications

References 30 publications

Methylglyoxal-Modified Human Serum Albumin Binds to Leukocyte Myeloperoxidase and Inhibits its Enzymatic Activity

Methylglyoxal-Modified Human Serum Albumin Binds to Leukocyte Myeloperoxidase and Inhibits its Enzymatic Activity

How the immune mousetrap works: structural evidence for the immunomodulatory action of a peptide from influenza NS1 protein

How the immune mousetrap works: Structural evidence for the immunomodulatory action of a peptide from influenza NS1 protein

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