PDF(Pubmed)
Abstract：
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 (Kd = 1.28 × 10-8 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 (Kd = 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.
摘要：
细胞因子的受体是免疫应答的主要调节因子。在这项工作中,我们发现了两个新的配体，可以激活TNFR1（肿瘤坏死因子受体1）受体。早些时候，我们发现标记肽（PGLYRP1）蛋白命名为17.1可以与TNFR1受体相互作用。这里,我们已经发现，Mts1（S100A4）蛋白与该肽相互作用具有高亲和力（Kd=1.28×10-8M），并且这种复合物对表面具有TNFR1受体的癌细胞具有细胞毒性。该复合物在线粒体和溶酶体参与细胞死亡信号转导的情况下诱导癌细胞的凋亡和坏死。此外，我们已经成功地定位了负责蛋白质-肽相互作用的Mts1片段，其与Tag7蛋白高度特异性地相互作用(Kd=2.96nM)。分离的Mts1肽M7也与17.1形成复合物,并且该肽-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显示了参与肽结合的氨基酸，可用于肽模拟物的开发。因此，产生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。
