Журнал генетических синдромов и генной терапии

Журнал генетических синдромов и генной терапии
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ISSN: ISSN: 2157-7412

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Identification of the Key Functional Domain of BAFF for Binding TACI by Computer-Guided Molecular Modeling Method

Ru Wang, Zhou Lin, Hui Peng, Huawei Wei, Xinying Li, Jian Sun, Jianmin Fang, Ning Li, Xiangbin Meng, Beifen Shen, Jiannan Feng and Yan Li

As an important member of the Tumor Necrosis Factor (TNF) super family, B cell activating factor (BAFF: also known as BLyS, TALL-1, THANK and zTNF4 or TNFSF13b) induces B cell proliferation and differentiation both in vivo and in vitro. A series of experimental results showed that the soluble form of a BAFF receptor, trans-membrane activator and CAML-interactor (TACI), could alleviate the autoimmune symptoms of NZBWF1 and MRL-lpr/lpr mice. Furthermore, the fusion protein TACI-Fc, as a novel BAFF antagonist, was used to the treatment of relapsing multiple sclerosis. However, it is not clear how BAFF interact with its receptor TACI. In this study, using the crystal structures of BAFF and its receptor TACI, the binding mode and the key domains of BAFF interaction with TACI were analyzed based on the computer-guided molecular modeling method. According to the theoretical predictions, a series of mutants of BAFF, including M1 (from Ile158 to Phe165), M2 (from Asp203 to Leu211), M3 (from Ser225 to Arg231) and M4 (from Ile233 to Glu238), were designed and evaluated with biological experiments. The results showed that the domains M2 and M4 of BAFF were the key domains interacting with TACI, which was in accord with our theoretical results. The results will highlight the clues for further development of novel BAFF inhibitors.
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