期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 49, 页码 19452-19457出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0709264104
关键词
crystal structure; T cell costimulation
资金
- NIAID NIH HHS [R01 AI007289, AI07289, R56 AI007289] Funding Source: Medline
- NIDDK NIH HHS [P30 DK020541, DK20541, P01 DK052956, R01 DK064315, R21 DK077500, DK065247, DK64315, DK77500, DK52956, P60 DK020541, R01 DK065247] Funding Source: Medline
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 approximate to 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.
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