Evolution of GITRL immune function: murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily.
Glucocorticoid-induced TNF receptor ligand (GITRL), a recently identified member of the TNF superfamily, 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. In contrast to all previously characterized homotrimeric TNF family members, the mouse GITRL crystal structure reveals a previously unrecognized dimeric assembly that is stabilized via a unique "domain-swapping" interaction. Consistent with its crystal structure, mouse GITRL exists as a stable dimer in solution. Structure-guided mutagenesis studies confirmed the determinants responsible for dimerization and support a previously unrecognized receptor-recognition surface for mouse GITRL that has not been observed for any other TNF family members. Taken together, the unique structural and biochemical behavior of mouse GITRL, along with the unusual domain organization of murine GITR, support a previously unrecognized mechanism for signaling within the TNF superfamily.
Chattopadhyay
Kausik
K
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Ramagopal
Udupi A
UA
Brenowitz
Michael
M
Nathenson
Stanley G
SG
Almo
Steven C
SC
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D019143:Evolution, Molecular; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007700:Kinetics; D051379:Mice; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors