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Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
Published on: September 21, 2011
Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function
Kausik Chattopadhyay1, Udupi A Ramagopal, Arunika Mukhopadhaya
1Departments of Microbiology and Immunology, Cell Biology, Biochemistry, Physiology and Biophysics, Medicine (Division of Endocrinology), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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 approximately 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.
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