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A Unique Zinc-Binding Site Revealed by a High-Resolution X-ray Structure of Homotrimeric Apo2L/TRAIL
Abstract
Apoptosis-inducing ligand 2 (Apo2L, also called TRAIL), a member of the tumor necrosis factor (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 A resolution and use alanine-scanning mutagenesis to map the receptor contact regions. The structure reveals a homotrimeric protein that resembles TNF with receptor-binding epitopes at the interface between monomers. A zinc ion is buried at the trimer interface, coordinated by the single cysteine residue of each monomer. The zinc ion is required for maintaining the native structure and stability and, hence, the biological activity of Apo2L. This is the first example of metal-dependent oligomerization and function of a cytokine.
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Citations
Cited by
Targeting death and decoy receptors of the tumour-necrosis factor superfamily
Ashkenazi, A. (2002) · Nature Reviews Cancer · doi:10.1038/nrc821 · Cited by 1,360
Self-citationApo2L/TRAIL-Dependent Recruitment of Endogenous FADD and Caspase-8 to Death Receptors 4 and 5
Kischkel, F. C., Lawrence, D. A., Chuntharapai, A., Schow, P., Kim, K. J., & Ashkenazi, A. (2000) · Immunity · doi:10.1016/s1074-7613(00)80212-5 · Cited by 975
Self-citationThe molecular architecture of the TNF superfamily
Bodmer, J.-L., Schneider, P., & Tschopp, J. (2002) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(01)01995-8 · Cited by 916
Apo2L/TRAIL and its death and decoy receptors
LeBlanc, H. N., & Ashkenazi, A. (2003) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401187 · Cited by 854
Self-citationZinc coordination sphere in biochemical zinc sites
Auld, D. S. (2001) · Biometals · doi:10.1023/a:1012976615056 · Cited by 721
Metadata
- Authors
- Hymowitz, S. G., O'Connell, M. P., Ultsch, M. H., Hurst, A., Totpal, K., Ashkenazi, A., de Vos, A. M., & Kelley, R. F.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2000-01-04
- Volume
- 39
- Issue
- 4
- Pages
- 633-640
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2119500275
- Cited by
- 261
- References
- 0
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: A Unique Zinc-Binding Site Revealed by a High-Resolution X-ray Structure of Homotrimeric Apo2L/TRAIL. https://app.cochat.ai/papers/10.1021/bi992242l
- The paper
- Hymowitz, S. G., O'Connell, M. P., Ultsch, M. H., Hurst, A., Totpal, K., Ashkenazi, A., de Vos, A. M., & Kelley, R. F. (2000). A Unique Zinc-Binding Site Revealed by a High-Resolution X-ray Structure of Homotrimeric Apo2L/TRAIL. Biochemistry. https://doi.org/10.1021/bi992242l
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