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

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 {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.

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959487
Report Number(s):
BNL-82473-2009-JA
Journal ID: ISSN 0027-8424; PNASA6; TRN: US201016%%631
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the USA; Journal Volume: 104; Journal Issue: 49
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; AFFINITY; LIGANDS; RECEPTORS; national synchrotron light source

Citation Formats

Chattopadhyay,K., Ramagopal, U., Mukhopadhaya, A., Malashkevich, V., DiLorenzo, T., Brenowitz, M., Nathenson, S., and Almo, S. Assembly and Structural Properties of Gluoccorticoid-Induced TNF Receptor Ligand: Implications for Function. United States: N. p., 2007. Web. doi:10.1073/pnas.0709264104.
Chattopadhyay,K., Ramagopal, U., Mukhopadhaya, A., Malashkevich, V., DiLorenzo, T., Brenowitz, M., Nathenson, S., & Almo, S. Assembly and Structural Properties of Gluoccorticoid-Induced TNF Receptor Ligand: Implications for Function. United States. doi:10.1073/pnas.0709264104.
Chattopadhyay,K., Ramagopal, U., Mukhopadhaya, A., Malashkevich, V., DiLorenzo, T., Brenowitz, M., Nathenson, S., and Almo, S. Mon . "Assembly and Structural Properties of Gluoccorticoid-Induced TNF Receptor Ligand: Implications for Function". United States. doi:10.1073/pnas.0709264104.
@article{osti_959487,
title = {Assembly and Structural Properties of Gluoccorticoid-Induced TNF Receptor Ligand: Implications for Function},
author = {Chattopadhyay,K. and Ramagopal, U. and Mukhopadhaya, A. and Malashkevich, V. and DiLorenzo, T. and Brenowitz, M. and Nathenson, S. and Almo, S.},
abstractNote = {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.},
doi = {10.1073/pnas.0709264104},
journal = {Proceedings of the National Academy of Sciences of the USA},
number = 49,
volume = 104,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}