Abstract
We have determined that the mutation of the cysteine-230 residue to either glycine or serine in TRAIL (tumour necrosis factor-alpha-related apoptosis-inducing ligand) results in the formation of a structurally incompetent dimer and a consequent loss of apoptotic activity. Similarly, chemical modification of the thiol residues present in both reduced and Zn(2+)-depleted trimer converts TRAIL into an inactive dimer. We postulate that cysteine-230 plays a critical role in homotrimerization of this tumoricidal cytokine.
Full Text
The Full Text of this article is available as a PDF (212.1 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alnemri E. S., Livingston D. J., Nicholson D. W., Salvesen G., Thornberry N. A., Wong W. W., Yuan J. Human ICE/CED-3 protease nomenclature. Cell. 1996 Oct 18;87(2):171–171. doi: 10.1016/s0092-8674(00)81334-3. [DOI] [PubMed] [Google Scholar]
- Ashkenazi A., Dixit V. M. Death receptors: signaling and modulation. Science. 1998 Aug 28;281(5381):1305–1308. doi: 10.1126/science.281.5381.1305. [DOI] [PubMed] [Google Scholar]
- Ashkenazi A., Pai R. C., Fong S., Leung S., Lawrence D. A., Marsters S. A., Blackie C., Chang L., McMurtrey A. E., Hebert A. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest. 1999 Jul;104(2):155–162. doi: 10.1172/JCI6926. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cha S. S., Kim M. S., Choi Y. H., Sung B. J., Shin N. K., Shin H. C., Sung Y. C., Oh B. H. 2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity. Immunity. 1999 Aug;11(2):253–261. doi: 10.1016/s1074-7613(00)80100-4. [DOI] [PubMed] [Google Scholar]
- Green D. R., Martin S. J. The killer and the executioner: how apoptosis controls malignancy. Curr Opin Immunol. 1995 Oct;7(5):694–703. doi: 10.1016/0952-7915(95)80079-4. [DOI] [PubMed] [Google Scholar]
- Hymowitz S. G., Christinger H. W., Fuh G., Ultsch M., O'Connell M., Kelley R. F., Ashkenazi A., de Vos A. M. Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol Cell. 1999 Oct;4(4):563–571. doi: 10.1016/s1097-2765(00)80207-5. [DOI] [PubMed] [Google Scholar]
- Hymowitz S. G., O'Connell M. P., Ultsch M. H., Hurst A., Totpal K., Ashkenazi A., de Vos A. M., Kelley R. F. A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL. Biochemistry. 2000 Feb 1;39(4):633–640. doi: 10.1021/bi992242l. [DOI] [PubMed] [Google Scholar]
- Jacobson M. D., Weil M., Raff M. C. Programmed cell death in animal development. Cell. 1997 Feb 7;88(3):347–354. doi: 10.1016/s0092-8674(00)81873-5. [DOI] [PubMed] [Google Scholar]
- MacFarlane M., Ahmad M., Srinivasula S. M., Fernandes-Alnemri T., Cohen G. M., Alnemri E. S. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J Biol Chem. 1997 Oct 10;272(41):25417–25420. doi: 10.1074/jbc.272.41.25417. [DOI] [PubMed] [Google Scholar]
- Mongkolsapaya J., Grimes J. M., Chen N., Xu X. N., Stuart D. I., Jones E. Y., Screaton G. R. Structure of the TRAIL-DR5 complex reveals mechanisms conferring specificity in apoptotic initiation. Nat Struct Biol. 1999 Nov;6(11):1048–1053. doi: 10.1038/14935. [DOI] [PubMed] [Google Scholar]
- Pitti R. M., Marsters S. A., Ruppert S., Donahue C. J., Moore A., Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996 May 31;271(22):12687–12690. doi: 10.1074/jbc.271.22.12687. [DOI] [PubMed] [Google Scholar]
- Rudin C. M., Thompson C. B. Apoptosis and disease: regulation and clinical relevance of programmed cell death. Annu Rev Med. 1997;48:267–281. doi: 10.1146/annurev.med.48.1.267. [DOI] [PubMed] [Google Scholar]
- Steller H. Mechanisms and genes of cellular suicide. Science. 1995 Mar 10;267(5203):1445–1449. doi: 10.1126/science.7878463. [DOI] [PubMed] [Google Scholar]
- Thompson C. B. Apoptosis in the pathogenesis and treatment of disease. Science. 1995 Mar 10;267(5203):1456–1462. doi: 10.1126/science.7878464. [DOI] [PubMed] [Google Scholar]
- Thornberry N. A., Lazebnik Y. Caspases: enemies within. Science. 1998 Aug 28;281(5381):1312–1316. doi: 10.1126/science.281.5381.1312. [DOI] [PubMed] [Google Scholar]
- Walczak H., Miller R. E., Ariail K., Gliniak B., Griffith T. S., Kubin M., Chin W., Jones J., Woodward A., Le T. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med. 1999 Feb;5(2):157–163. doi: 10.1038/5517. [DOI] [PubMed] [Google Scholar]
- 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. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995 Dec;3(6):673–682. doi: 10.1016/1074-7613(95)90057-8. [DOI] [PubMed] [Google Scholar]