Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 2, Pages 635-640Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0710529105
Keywords
crystal structure; domain swap; oligomerization; T cell costimulation
Categories
Funding
- NCI NIH HHS [P30CA13330, P30 CA013330] Funding Source: Medline
- NIAID NIH HHS [R56 AI007289, AI07289, R01 AI007289] Funding Source: Medline
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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.
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