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.
Departments of Microbiology and Immunology, Cell Biology, Biochemistry, Physiology and Biophysics, Medicine (Division of Endocrinology), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Kausik
K
Chattopadhyay
Udupi A
UA
Ramagopal
Arunika
A
Mukhopadhaya
Vladimir N
VN
Malashkevich
Teresa P
TP
Dilorenzo
Michael
M
Brenowitz
Stanley G
SG
Nathenson
Steven C
SC
Almo
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