A Unique Zinc-Binding Site Revealed by a High-Resolution X-ray Structure of Homotrimeric Apo2L/TRAIL

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• 作者：Sarah G. Hymowitz ; Mark P. O'Connell ; Mark H. Ultsch ; Amy Hurst ; Klara Totpal ; Avi Ashkenazi ; Abraham M. de Vos ; and Robert F. Kelley
• 刊名：Biochemistry
• 出版年：2000
• 出版时间：February 1, 2000
• 年：2000
• 卷：39
• 期：4
• 页码：633 - 640
• 全文大小：524K
• 年卷期：v.39,no.4(February 1, 2000)
• ISSN：1520-4995

文摘

Apoptosis-inducing ligand 2 (Apo2L, also called TRAIL), a member of the tumor necrosisfactor (TNF) family, induces apoptosis in a variety of human tumor cell lines but not in normal cells[Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C.-P., Nicholl, J. K., Sutherland, G. R.,Smith, T. D., Rauch, C., Smith, C. A., and Goodwin, R. G. (1995) Immunity 3, 673-682; Pitti, R. M.,Marsters, S. A., Ruppert, S., Donahue, C. J., Moore, A., and Ashkenazi, A. (1996) J. Biol. Chem. 271,12687-12690]. Here we describe the structure of Apo2L at 1.3 Å resolution and use alanine-scanningmutagenesis to map the receptor contact regions. The structure reveals a homotrimeric protein that resemblesTNF with receptor-binding epitopes at the interface between monomers. A zinc ion is buried at the trimerinterface, coordinated by the single cysteine residue of each monomer. The zinc ion is required formaintaining the native structure and stability and, hence, the biological activity of Apo2L. This is thefirst example of metal-dependent oligomerization and function of a cytokine.