Institute of Gene Biology (RAS), Moscow 119334, Russia.
Institute of Biomedical Chemistry, Pogodinskaya Street 10, Moscow 119121, Russia.
Int J Mol Sci. 2024 Jun 16;25(12):6633. doi: 10.3390/ijms25126633.
Receptors of cytokines are major regulators of the immune response. In this work, we have discovered two new ligands that can activate the TNFR1 (tumor necrosis factor receptor 1) receptor. Earlier, we found that the peptide of the Tag (PGLYRP1) protein designated 17.1 can interact with the TNFR1 receptor. Here, we have found that the Mts1 (S100A4) protein interacts with this peptide with a high affinity (K = 1.28 × 10 M), and that this complex is cytotoxic to cancer cells that have the TNFR1 receptor on their surface. This complex induces both apoptosis and necroptosis in cancer cells with the involvement of mitochondria and lysosomes in cell death signal transduction. Moreover, we have succeeded in locating the Mts1 fragment that is responsible for protein-peptide interaction, which highly specifically interacts with the Tag7 protein (K = 2.96 nM). The isolated Mts1 peptide M7 also forms a complex with 17.1, and this peptide-peptide complex also induces the TNFR1 receptor-dependent cell death. Molecular docking and molecular dynamics experiments show the amino acids involved in peptide binding and that may be used for peptidomimetics' development. Thus, two new cytotoxic complexes were created that were able to induce the death of tumor cells via the TNFR1 receptor. These results may be used in therapy for both cancer and autoimmune diseases.
细胞因子受体是免疫反应的主要调节剂。在这项工作中，我们发现了两种可以激活 TNFR1（肿瘤坏死因子受体 1）受体的新配体。早些时候，我们发现了标记蛋白（PGLYRP1）的肽 17.1 可以与 TNFR1 受体相互作用。在这里，我们发现 Mts1（S100A4）蛋白与该肽具有高亲和力（K = 1.28 × 10 M）相互作用，并且该复合物对表面具有 TNFR1 受体的癌细胞具有细胞毒性。该复合物通过线粒体和溶酶体参与细胞死亡信号转导，诱导癌细胞凋亡和坏死。此外，我们成功定位了负责蛋白-肽相互作用的 Mts1 片段，该片段与 Tag7 蛋白高度特异性相互作用（K = 2.96 nM）。分离的 Mts1 肽 M7 也与 17.1 形成复合物，该肽-肽复合物也诱导 TNFR1 受体依赖性细胞死亡。分子对接和分子动力学实验表明了参与肽结合的氨基酸，这些氨基酸可能用于开发肽模拟物。因此，创建了两种新的细胞毒性复合物，它们能够通过 TNFR1 受体诱导肿瘤细胞死亡。这些结果可用于癌症和自身免疫性疾病的治疗。
