Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function
- Kausik Chattopadhyay*,
- Udupi A. Ramagopal†,
- Arunika Mukhopadhaya*,
- Vladimir N. Malashkevich†,
- Teresa P. DiLorenzo*,‡,
- Michael Brenowitz†,
- Stanley G. Nathenson*,§,¶, and
- Steven C. Almo†,¶,‖
- Departments of *Microbiology and Immunology,
- §Cell Biology,
- †Biochemistry,
- ‖Physiology and Biophysics,
- ‡Medicine (Division of Endocrinology), Albert Einstein College of Medicine, Bronx, NY 10461
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Contributed by Stanley G. Nathenson, September 28, 2007 (received for review August 3, 2007)
Abstract
Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF family, binds to its receptor GITR on both effector and regulatory T cells and generates positive costimulatory signals implicated in a wide range of T cell functions. Structural analysis reveals that the human GITRL (hGITRL) ectodomain self-assembles into an atypical expanded homotrimer with sparse monomer–monomer interfaces. Consistent with the small intersubunit interfaces, hGITRL exhibits a relatively weak tendency to trimerize in solution and displays a monomer–trimer equilibrium not reported for other TNF family members. This unique assembly behavior has direct implications for hGITRL–GITR signaling, because enforced trimerization of soluble hGITRL ectodomain results in an ≈100-fold increase in its receptor binding affinity and also in enhanced costimulatory activity. The apparent reduction in affinity that is the consequence of this dynamic equilibrium may represent a mechanism to realize the biologically optimal level of signaling through the hGITRL–GITR pathway, as opposed to the maximal achievable level.
Footnotes
- ¶To whom correspondence may be addressed. E-mail: nathenso{at}aecom.yu.edu or almo{at}aecom.yu.edu
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Author contributions: K.C., A.M., T.P.D., M.B., S.G.N., and S.C.A. designed research; K.C., U.A.R., A.M., and M.B. performed research; K.C. and V.N.M. contributed new reagents/analytic tools; K.C., U.A.R., A.M., and M.B. analyzed data; K.C., S.G.N., and S.C.A. wrote the paper.
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The authors declare no conflict of interest.
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Data deposition: The structure factors and coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 2Q1M, 2R30, and 2R32).
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This article contains supporting information online at www.pnas.org/cgi/content/full/0709264104/DC1.
- © 2007 by The National Academy of Sciences of the USA
