Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function

Kausik Chattopadhyay, Udupi A. Ramagopal, Arunika Mukhopadhaya, Vladimir N. Malashkevich, Teresa P. DiLorenzo, Michael Brenowitz, Stanley G. Nathenson, Steven C. Almo

Research output: Contribution to journalArticle

54 Scopus citations

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 ≈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.

Original languageEnglish (US)
Pages (from-to)19452-19457
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number49
DOIs
StatePublished - Dec 4 2007

Keywords

  • Crystal structure
  • T cell costimulation

ASJC Scopus subject areas

  • General

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