Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia.
Department of Molecular, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Biomolecules. 2023 Sep 4;13(9):1345. doi: 10.3390/biom13091345.
S100 is a family of over 20 structurally homologous, but functionally diverse regulatory (calcium/zinc)-binding proteins of vertebrates. The involvement of S100 proteins in numerous vital (patho)physiological processes is mediated by their interaction with various (intra/extra)cellular protein partners, including cell surface receptors. Furthermore, recent studies have revealed the ability of specific S100 proteins to modulate cell signaling via direct interaction with cytokines. Previously, we revealed the binding of ca. 71% of the four-helical cytokines via the S100P protein, due to the presence in its molecule of a cytokine-binding site overlapping with the binding site for the S100P receptor. Here, we show that another S100 protein, S100A6 (that has a pairwise sequence identity with S100P of 35%), specifically binds numerous four-helical cytokines. We have studied the affinity of the recombinant forms of 35 human four-helical cytokines from all structural families of this fold to Ca-loaded recombinant human S100A6, using surface plasmon resonance spectroscopy. S100A6 recognizes 26 of the cytokines from all families of this fold, with equilibrium dissociation constants from 0.3 nM to 12 µM. Overall, S100A6 interacts with ca. 73% of the four-helical cytokines studied to date, with a selectivity equivalent to that for the S100P protein, with the differences limited to the binding of interleukin-2 and oncostatin M. The molecular docking study evidences the presence in the S100A6 molecule of a cytokine-binding site, analogous to that found in S100P. The findings argue the presence in some of the promiscuous members of the S100 family of a site specific to a wide range of four-helical cytokines. This unique feature of the S100 proteins potentially allows them to modulate the activity of the numerous four-helical cytokines in the disorders accompanied by an excessive release of the cytokines.
S100 是脊椎动物中超过 20 种结构同源但功能多样的调节钙/锌结合蛋白家族。S100 蛋白通过与各种细胞内/外蛋白伴侣（包括细胞表面受体）相互作用，参与许多重要的（病理）生理过程。此外，最近的研究表明，特定的 S100 蛋白能够通过与细胞因子的直接相互作用来调节细胞信号。之前，我们发现由于 S100P 分子中存在与 S100P 受体结合位点重叠的细胞因子结合位点，约 71%的四螺旋细胞因子与 S100P 结合。在这里，我们展示了另一种 S100 蛋白 S100A6 特异性结合许多四螺旋细胞因子。我们使用表面等离子体共振光谱法研究了来自该折叠所有结构家族的 35 个人类四螺旋细胞因子的重组形式与 Ca 负载的重组人 S100A6 的亲和力。S100A6 识别来自该折叠所有家族的 26 种细胞因子，平衡解离常数为 0.3 nM 至 12 µM。总的来说，S100A6 与迄今为止研究过的约 73%的四螺旋细胞因子相互作用，其选择性与 S100P 蛋白相当，差异仅限于白细胞介素-2 和肿瘤坏死因子 M 的结合。分子对接研究表明，S100A6 分子中存在类似于 S100P 中发现的细胞因子结合位点。这些发现表明，在 S100 家族的一些混杂成员中存在一个针对广泛的四螺旋细胞因子的特异性位点。S100 蛋白的这一独特特征可能使它们能够调节在细胞因子过度释放伴随的疾病中众多四螺旋细胞因子的活性。
