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首页> 外文期刊>Biochemistry >ANALYSIS OF GP39/CD40 INTERACTIONS USING MOLECULAR MODELS AND SITE-DIRECTED MUTAGENESIS
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ANALYSIS OF GP39/CD40 INTERACTIONS USING MOLECULAR MODELS AND SITE-DIRECTED MUTAGENESIS

机译：使用分子模型和定向诱变分析GP39 / CD40相互作用

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摘要

The interaction between gp39 (CD40L, TRAP, T-BAM) on activated T cells and mast cells and CD40 on antigen-presenting cells modulates immune responses. Gp39 and CD40 are homologous to tumor necrosis factor (TNF) and its receptor (TNFR), respectively. The TNF-beta/TNFR interaction has been analyzed on the basis of mutagenesis experiments and crystal structures. Using the interaction of TNF-beta/TNFR as a guide, we previously reported a site-directed mutagenesis study in which we identified residues in gp39 (K143, Y145) and CD40 (Y82, D84, N86) involved in gp39/CD40 interactions. Here we describe the use of the TNF-beta/TNFR complex crystal structure as a template to prepare molecular models of gp39, CD40, and their approximate interaction. The application of these models has allowed us to extend our mutagenesis analysis of gp39/CD40 interactions, These experiments have led to the identification of additional gp39 (Y146, R203, Q220) and CD40 (E74, E117) residues that contribute to the gp39/CD40 interaction. We also further explored the importance of gp39 residue Y145 and CD40 residue Y82 for the gp39/CD40 interaction by conservatively replacing these residues with Phe. The results of these studies have enabled us to approximately outline the binding sites in gp39 and CD40. It appears that the gp39/CD40 interaction is centered on at least two clusters of residues and involves residues of two adjacent gp39 monomers. The molecular regions involved in the gp39/CD40 interaction essentially correspond to those in the homologous TNF-beta/TNFR system.
机译：活化的T细胞和肥大细胞上的gp39（CD40L，TRAP，T-BAM）和抗原呈递细胞上的CD40之间的相互作用调节免疫应答。 Gp39和CD40分别与肿瘤坏死因子（TNF）及其受体（TNFR）同源。 TNF-β/ TNFR相互作用已在诱变实验和晶体结构的基础上进行了分析。以TNF-beta / TNFR的相互作用为指导，我们先前报道了一项定点诱变研究，其中我们鉴定了gp39（K143，Y145）和CD40（Y82，D84，N86）中参与gp39 / CD40相互作用的残基。在这里，我们描述了使用TNF-β/ TNFR复合物晶体结构作为模板来制备gp39，CD40及其近似相互作用的分子模型。这些模型的应用使我们能够扩展对gp39 / CD40相互作用的诱变分析。这些实验已导致鉴定出其他有助于gp39 /的gp39（Y146，R203，Q220）和CD40（E74，E117）残基CD40相互作用。我们还通过保守地用Phe取代了这些残基，进一步探索了gp39残基Y145和CD40残基Y82对于gp39 / CD40相互作用的重要性。这些研究的结果使我们能够大致概述gp39和CD40中的结合位点。似乎gp39 / CD40相互作用集中在至少两个残基簇上，并且涉及两个相邻gp39单体的残基。参与gp39 / CD40相互作用的分子区域基本上对应于同源TNF-beta / TNFR系统中的分子区域。

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