Assembly and Structural Properties of Gluoccorticoid-Induced TNF Receptor Ligand: Implications for Function

Journal Article · Mon Jan 01 04:00:00 EST 2007 · Proceedings of the National Academy of Sciences of the USA

DOI:https://doi.org/10.1073/pnas.0709264104· OSTI ID:959487

Chattopadhyay, K; Ramagopal, U; Mukhopadhaya, A; Malashkevich, V; DiLorenzo, T; Brenowitz, M; Nathenson, S; Almo, S

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 {approx}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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 959487
• Report Number(s): BNL--82473-2009-JA
• Journal Information: Proceedings of the National Academy of Sciences of the USA, Journal Name: Proceedings of the National Academy of Sciences of the USA Journal Issue: 49 Vol. 104; ISSN 0027-8424; ISSN PNASA6
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
AFFINITY
LIGANDS
RECEPTORS
national synchrotron light source