TY - JOUR
T1 - Evolution of GITRL immune function
T2 - Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily
AU - Chattopadhyay, Kausik
AU - Ramagopal, Udupi A.
AU - Brenowitz, Michael
AU - Nathenson, Stanley G.
AU - Almo, Steven C.
PY - 2008/1/15
Y1 - 2008/1/15
N2 - 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.
AB - 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.
KW - Crystal structure
KW - Domain swap
KW - Oligomerization
KW - T cell costimulation
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U2 - 10.1073/pnas.0710529105
DO - 10.1073/pnas.0710529105
M3 - Article
C2 - 18182486
AN - SCOPUS:38649090326
SN - 0027-8424
VL - 105
SP - 635
EP - 640
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 2
ER -