Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function
Year: 2007
Type: article
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 approximately 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.
Institution: Albert Einstein College of Medicine
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G160588057, G2387304815, Preservation & Replacement of Beta Cells in IDDM, CD8 T Cell Reactivity to IGRP as an Autoimmunity Marker in Type 1 Diabetes, G4405391965, G4975832815, G5021689401, Mechanisms of beta2-microglubin in Autoimmune Diabetes, G630845642, Molecular and Structural Basis for T Cell Costimulation, Diabetes Research and Training Center, Antigens Recognized by CD8+ T Cells in Type 1 Diabetes, Molecular and Structural Basis for T Cell Costimulation, G9000208100, NYR-Diabetes Research Center (NYR-DRC)
OpenAlex ID: W2007868209