Biochemical and Structural Characterization of the Human TL1A Ectodomain,

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• 作者：Chenyang Zhan ; Qingrong Yan ; Yury Patskovsky ; Zhenhong Li ; Rafael Toro ; Amanda Meyer ; Huiyong Cheng ; Michael Brenowitz ; Stanley G. Nathenson ; Steven C. Almo
• 刊名：Biochemistry
• 出版年：2009
• 出版时间：August 18, 2009
• 年：2009
• 卷：48
• 期：32
• 页码：7636-7645
• 全文大小：1060K
• 年卷期：v.48,no.32(August 18, 2009)
• ISSN：1520-4995

文摘

TNF-like 1A (TL1A) is a newly described member of the TNF superfamily that is directly implicated in the pathogenesis of autoimmune diseases, including inflammatory bowel disease, atherosclerosis, and rheumatoid arthritis. We report the crystal structure of the human TL1A extracellular domain at a resolution of 2.5 Å, which reveals a jelly-roll fold typical of the TNF superfamily. This structural information, in combination with complementary mutagenesis and biochemical characterization, provides insights into the binding interface and the specificity of the interactions between TL1A and the DcR3 and DR3 receptors. These studies suggest that the mode of interaction between TL1A and DcR3 differs from other characterized TNF ligand/receptor complexes. In addition, we have generated functional TL1A mutants with altered disulfide bonding capability that exhibit enhanced solution properties, which will facilitate the production of materials for future cell-based and whole animal studies. In summary, these studies provide insights into the structure and function of TL1A and provide the basis for the rational manipulation of its interactions with cognate receptors.