Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function.
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.
Chattopadhyay
Kausik
K
Departments of Microbiology and Immunology, Cell Biology, Biochemistry, Physiology and Biophysics, Medicine (Division of Endocrinology), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Ramagopal
Udupi A
UA
Mukhopadhaya
Arunika
A
Malashkevich
Vladimir N
VN
Dilorenzo
Teresa P
TP
Brenowitz
Michael
M
Nathenson
Stanley G
SG
Almo
Steven C
SC
D001665:Binding Sites; D018360:Crystallography, X-Ray; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D009154:Mutation; D011487:Protein Conformation; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry; D012996:Solutions; D048069:Tumor Necrosis Factors / Q000737:chemistry* / Q000235:genetics
D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D012996:Solutions; C491405:TNFRSF18 protein, human; C478967:TNFSF18 protein, human; D048069:Tumor Necrosis Factors