An Exception to the Trimer Paradigm

Abstract

The tumor necrosis factor (TNF) superfamily is a large and diverse group of ligands involved in various biological processes. All previously characterized members of this family adopted a trimeric active structure that interacted in a 3:3 ligand:receptor stoichiometry with the cognate receptor. Two groups (Chattopadhyay et al . and Zhou et al .) report that mouse glucocorticoid-induced tumor necrosis factor receptor ligand (mGITRL) adopts a dimeric structure. Both groups crystallized the ectodomain of mGITRL (TNF ligands are synthesized as transmembrane proteins that either act on adjacent cells or are cleaved into soluble forms) and found that it formed a dimer with domain swap regions that formed intermolecular β sheets composed of the C terminus of one subunit and an inner β sheet of the other. Mutation and deletion analysis indicated that this C-terminal region was critical for formation of the dimer. The dimer was confirmed by sedimentation analysis. Exactly how this dimeric ligand interacts with the receptor GITR remains an open question. GITRL:GITR signaling is important in modulating immune responses, although mouse GITRL (dimeric) and human GITRL (trimeric) appear to play different roles and do not substitute for one another, suggesting species-specific evolution of structure and function. K. Chattopadhyay, U. A. Ramagopal, M. Brenowitz, S. G. Nathenson, S. C. Almo, Evolution of GITRL immune function: Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily. Proc. Nat. Acad. Sci. U.S.A. 105 , 635-640 (2008). [Abstract] [Full Text] Z. Zhou, Y. Tone, X. Song, K. Furuuchi, J. D. Lear, H. Waldmann, M . Tone, M. I. Greene, R. Murali, Structural basis for ligand-mediated mouse GITR activation. Proc. Nat. Acad. Sci. U.S.A. 105 , 641-645 (2008). [Abstract] [Full Text]