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J. Biol. Chem. 275 (30): 23319-23325

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Temperature-sensitive Differential Affinity of TRAIL for Its Receptors
DR5 IS THE HIGHEST AFFINITY RECEPTOR*

Alemseged TrunehDagger §, Sunita SharmaDagger ||, Carol Silverman||**, Sanjay Khandekar**, Manjula P. ReddyDagger , Keith C. DeenDagger , Megan M. MclaughlinDagger Dagger , Srinivasa M. Srinivasula§§, George P. LiviDagger Dagger , Lisa A. MarshallDagger , Emad S. Alnemri§§, William V. Williams, and Michael L. Doyle¶¶

From the Departments of Dagger  Immunology, ** Protein Biochemistry, Dagger Dagger  Comparative Genetics, and ¶¶ Structural Biology and the  Clinical Pharmacology Unit, SmithKline Beecham Pharmaceuticals, Pennsylvania, King of Prussia and §§ Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines which induces apoptotic cell death in a variety of tumor cell lines. It mediates its apoptotic effects through one of two receptors, DR4 and DR5, which are members of of the TNF receptor family, and whose cytoplasmic regions contain death domains. In addition, TRAIL also binds to 3 "decoy" receptors, DcR2, a receptor with a truncated death domain, DcR1, a glycosylphosphatidylinositol-anchored receptor, and OPG a secreted protein which is also known to bind to another member of the TNF family, RANKL. However, although apoptosis depends on the expression of one or both of the death domain containing receptors DR4 and/or DR5, resistance to TRAIL-induced apoptosis does not correlate with the expression of the "decoy" receptors. Previously, TRAIL has been described to bind to all its receptors with equivalent high affinities. In the present work, we show, by isothermal titration calorimetry and competitive enzyme-linked immunosorbent assay, that the rank order of affinities of TRAIL for the recombinant soluble forms of its receptors is strongly temperature dependent. Although DR4, DR5, DcR1, and OPG show similar affinities for TRAIL at 4 °C, their rank-ordered affinities are substantially different at 37 °C, with DR5 having the highest affinity (KD <=  2 nM) and OPG having the weakest (KD = 400 nM). Preferentially enhanced binding of TRAIL to DR5 was also observed at the cell surface. These results reveal that the rank ordering of affinities for protein-protein interactions in general can be a strong function of temperature, and indicate that sizeable, but hitherto unobserved, TRAIL affinity differences exist at physiological temperature, and should be taken into account in order to understand the complex physiological and/or pathological roles of TRAIL.

* This work was supported by National Institutes of Health Grant CA78890 (to E. S. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| Contributed equally to the results of this work.

§ To whom correspondence should be addressed: Dept. of Immunology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd., King of Prussia, PA 19406. Tel.: 610-270-4884; Fax: 610-270-5114; E-mail: alem_truneh@sbphrd.com.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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