Binding of Specific S100 Proteins Inhibits Activity of Tumor Necrosis Factor

Alexey S. Kazakov; Marina Y. Zemskova; Gleb K. Rystsov; Alisa A. Vologzhannikova; Evgenia I. Deryusheva; Victoria A. Rastrygina; Andrey S. Sokolov; Maria E. Permyakova; Ekaterina A. Litus; Vladimir N. Uversky; Eugene A. Permyakov; Sergei E. Permyakov

doi:10.20944/preprints202211.0313.v1

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preprints.org > biology and life sciences > biophysics > doi: 10.20944/preprints202211.0313.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Binding of Specific S100 Proteins Inhibits Activity of Tumor Necrosis Factor

Alexey S. Kazakov

Marina Y. Zemskova

Gleb K. Rystsov

Alisa A. Vologzhannikova

Evgenia I. Deryusheva

Victoria A. Rastrygina

^* ,

Version 1 : Received: 15 November 2022 / Approved: 16 November 2022 / Online: 16 November 2022 (13:12:59 CET)

A peer-reviewed article of this Preprint also exists.

Kazakov, A.S.; Zemskova, M.Y.; Rystsov, G.K.; Vologzhannikova, A.A.; Deryusheva, E.I.; Rastrygina, V.A.; Sokolov, A.S.; Permyakova, M.E.; Litus, E.A.; Uversky, V.N.; Permyakov, E.A.; Permyakov, S.E. Specific S100 Proteins Bind Tumor Necrosis Factor and Inhibit Its Activity. Int. J. Mol. Sci. 2022, 23, 15956. Kazakov, A.S.; Zemskova, M.Y.; Rystsov, G.K.; Vologzhannikova, A.A.; Deryusheva, E.I.; Rastrygina, V.A.; Sokolov, A.S.; Permyakova, M.E.; Litus, E.A.; Uversky, V.N.; Permyakov, E.A.; Permyakov, S.E. Specific S100 Proteins Bind Tumor Necrosis Factor and Inhibit Its Activity. Int. J. Mol. Sci. 2022, 23, 15956.

Abstract

Tumor necrosis factor (TNF) inhibitors (anti-TNFs) represent a cornerstone of the treatment of various immune-mediated inflammatory diseases and are among the most commercially successful therapeutic agents. Knowledge of TNF binding partners is critical for identification of the factors able to affect clinical efficacy of the anti-TNFs. Here we report that among eighteen representatives of the multifunctional S100 protein family only S100A11, S100A12 and S100A13 interact with the soluble form of TNF (sTNF) in vitro. The lowest equilibrium dissociation constants (Kd) for the complexes with monomeric sTNF determined using surface plasmon resonance spectroscopy range from 2 nM to 28 nM. The apparent Kd values for the complexes of multimeric sTNF with S100A11/A12 estimated from fluorimetric titrations are 0.1-0.3 µM. S100A12/A13 suppress the cytotoxic activity of sTNF against Huh-7 cells, as evidenced by the MTT assay. Structural modeling indicates that the sTNF-S100 interactions may interfere with the sTNF recognition by the therapeutic anti-TNFs. Bioinformatic analysis reveals dysregulation of TNF and S100A11/A12/A13 in numerous disorders. Overall, we have shown a novel potential regulatory role of the extracellular forms of specific S100 proteins that may affect efficacy of anti-TNF treatment in various diseases.

Keywords

cytokine; Tumor necrosis factor; S100 protein; protein–protein interaction; inflammatory diseases

Subject

Biology and Life Sciences, Biophysics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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