Soluble form of tumor necrosis factor-related apoptosis-inducing ligand interacts with S100P protein.

Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) is a therapeutically relevant protein belonging to the TNF superfamily. Both membrane-bound and soluble (sTRAIL) forms of TRAIL affect innate and adaptive immune responses. We recently showed that soluble TNF binds specific members of the S100 family of multifunctional calcium-binding proteins, leading to suppression of its cytotoxic activity (Int. J. Mol. Sci. 2022, 23(24), 15,956). To test the ability of S100 proteins to affect sTRAIL functioning, we used surface plasmon resonance spectroscopy, intrinsic fluorescence, chemical crosslinking, molecular modeling, site-directed mutagenesis, cytotoxicity assay, and bioinformatics to study interaction of human sTRAIL with human non-fused S100 proteins. Of the 21 S100 proteins examined, only S100P protein showed specific interaction with sTRAIL characterized by equilibrium dissociation constant, K, reaching (0.16 ± 0.07) μM. sTRAIL monomer binds dimeric S100P strictly in the presence of Ca, while sTRAIL trimer interacts with S100P dimer regardless of Ca. Site-directed mutagenesis confirmed involvement of the 'hinge' and C-terminal regions of S100P in the sTRAIL recognition, consistent with the structural modeling results. Bioinformatic analysis indicates dysregulation of TRAIL and S100P in various neoplasms. S100P lowers cytotoxicity of sTRAIL against human fibrosarcoma HT-1080 cells. The suppression of proapoptotic sTRAIL signaling by S100P protein may contribute to oncogenic effects of the latter.

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