Evolution of GITRL immune function

Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily

Kausik Chattopadhyay, Udupi A. Ramagopal, Michael D. Brenowitz, Stanley G. Nathenson, Steven C. Almo

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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 "-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.

Original languageEnglish (US)
Pages (from-to)635-640
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number2
DOIs
StatePublished - Jan 15 2008

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Tumor Necrosis Factors
Glucocorticoids
Dimerization
Regulatory T-Lymphocytes
Mutagenesis
T-Lymphocytes

Keywords

  • Crystal structure
  • Domain swap
  • Oligomerization
  • T cell costimulation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Evolution of GITRL immune function : Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily. / Chattopadhyay, Kausik; Ramagopal, Udupi A.; Brenowitz, Michael D.; Nathenson, Stanley G.; Almo, Steven C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 2, 15.01.2008, p. 635-640.

Research output: Contribution to journalArticle

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