Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Recognition of Granulocyte-Macrophage Colony-Stimulating Factor by Specific S100 Proteins

Version 1 : Received: 31 October 2023 / Approved: 1 November 2023 / Online: 1 November 2023 (08:49:05 CET)
Version 2 : Received: 10 November 2023 / Approved: 13 November 2023 / Online: 13 November 2023 (08:40:41 CET)

A peer-reviewed article of this Preprint also exists.

Kazakov, A.S.; Rastrygina, V.A.; Vologzhannikova, A.A.; Zemskova, M.Y.; Bobrova, L.A.; Deryusheva, E.I.; Permyakova, M.E.; Sokolov, A.S.; Litus, E.A.; Shevelyova, M.P.; et al. Recognition of Granulocyte-Macrophage Colony-Stimulating Factor by Specific S100 Proteins. Cell Calcium 2024, 102869, doi:10.1016/j.ceca.2024.102869. Kazakov, A.S.; Rastrygina, V.A.; Vologzhannikova, A.A.; Zemskova, M.Y.; Bobrova, L.A.; Deryusheva, E.I.; Permyakova, M.E.; Sokolov, A.S.; Litus, E.A.; Shevelyova, M.P.; et al. Recognition of Granulocyte-Macrophage Colony-Stimulating Factor by Specific S100 Proteins. Cell Calcium 2024, 102869, doi:10.1016/j.ceca.2024.102869.

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic myelopoietic growth factor and proinflammatory cytokine, clinically used for multiple indications and serving as a promising target for treatment of many disorders, including cancer, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, COVID-19. We have previously shown that dimeric Ca2+-bound forms of S100A6 and S100P proteins, members of the multifunctional S100 protein family, are specific to GM-CSF. To probe selectivity of these interactions, the affinity of recombinant human GM-CSF to dimeric Ca2+-loaded forms of 18 recombinant human S100 proteins was studied by surface plasmon resonance spectroscopy. Of them, only S100A4 protein specifically binds to GM-CSF with equilibrium dissociation constant, Kd, values of 0.3-2 μM, as confirmed by intrinsic fluorescence and chemical crosslinking data. Calcium removal prevents S100A4 binding to GM-CSF, whereas monomerization of S100A4/A6/P proteins disrupts S100A4/A6 interaction with GM-CSF and induces a slight decrease in S100P affinity for GM-CSF. Structural modelling indicates the presence in the GM-CSF molecule of a conserved S100A4/A6/P-binding site, consisting of the residues from its termini, helices I and III, some of which are involved in the interaction with GM-CSF receptors. The predicted involvement of the ‘hinge’ region and F89 residue of S100P in GM-CSF recognition was confirmed by mutagenesis. Examination of S100A4/A6/P ability to affect GM-CSF signaling showed that S100A4/A6 inhibit GM-CSF/S100-induced suppression of viability of monocytic THP-1 cells. The ability of the S100 proteins to modulate GM-CSF activity is relevant to progression of various neoplasms and other diseases, according to bioinformatic analysis. The direct regulation of GM-CSF signaling by extracellular forms of the S100 proteins should be taken into account in the clinical use of GM-CSF and development of the therapeutic interventions targeting GM-CSF or its receptors.

Keywords

GM-CSF; S100A4; S100A6; S100P; protein–protein interaction; cell viability

Subject

Biology and Life Sciences, Life Sciences

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.