TY - JOUR
T1 - Mechanistic basis for functional promiscuity in the TNF and TNF Receptor superfamilies
T2 - Structure of the light:DcR3 assembly
AU - Liu, Weifeng
AU - Zhan, Chenyang
AU - Cheng, Huiyong
AU - Kumar, P. Rajesh
AU - Bonanno, Jeffrey B.
AU - Nathenson, Stanley G.
AU - Almo, Steven C.
N1 - Funding Information:
We thank the staff of X29A beamlines at the National Synchrotron Light Source for the help. Use of the National Synchrotron Light Source, Brookhaven National Laboratory, was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. DE-AC02-98CH10886. Data for this study were measured at beamline X29A of the National Synchrotron Light Source. Financial support comes principally from the Office of Biological and Environmental Research and the Office of Basic Energy Sciences of the U.S. Department of Energy, from the National Center for Research Resources (P41RR012408), and from the National Institute of General Medical Sciences (P41GM103473). We also thank Dr. Steven M. Larson for providing the HT-29 cell line and Dr. Teresa DiLorenzo for critical reading of the manuscript. This work was supported by National Institute of General Medical Science grants GM094662 and GM094665 (to S.C.A.). The Albert Einstein Cancer Center is supported by NIH grant P30CA013330. This work was partially supported by contributions to the Albert Einstein Center for Experimental Therapeutics by Pamela and Edward S. Pantzer.
PY - 2014/9/2
Y1 - 2014/9/2
N2 - LIGHT initiates intracellular signaling via engagement of the two TNF receptors, HVEM and LTβR. In humans, LIGHT is neutralized by DcR3, a unique soluble member of the TNFR superfamily, which tightly binds LIGHT and inhibits its interactions with HVEM and LTβR. DcR3 also neutralizes two other TNF ligands, FasL and TL1A. Due to its ability to neutralize three distinct different ligands, DcR3 contributes to a wide range of biological and pathological processes, including cancer and autoimmune diseases. However, the mechanisms that support the broad specificity of DcR3 remain to be fully defined. We report the structures of LIGHT and the LIGHT:DcR3 complex, which reveal the structural basis for the DcR3-mediated neutralization of LIGHT and afford insights into DcR3 function and binding promiscuity. Based on these structures, we designed LIGHT mutants with altered affinities for DcR3 and HVEM, which may represent mechanistically informative probe reagents.
AB - LIGHT initiates intracellular signaling via engagement of the two TNF receptors, HVEM and LTβR. In humans, LIGHT is neutralized by DcR3, a unique soluble member of the TNFR superfamily, which tightly binds LIGHT and inhibits its interactions with HVEM and LTβR. DcR3 also neutralizes two other TNF ligands, FasL and TL1A. Due to its ability to neutralize three distinct different ligands, DcR3 contributes to a wide range of biological and pathological processes, including cancer and autoimmune diseases. However, the mechanisms that support the broad specificity of DcR3 remain to be fully defined. We report the structures of LIGHT and the LIGHT:DcR3 complex, which reveal the structural basis for the DcR3-mediated neutralization of LIGHT and afford insights into DcR3 function and binding promiscuity. Based on these structures, we designed LIGHT mutants with altered affinities for DcR3 and HVEM, which may represent mechanistically informative probe reagents.
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U2 - 10.1016/j.str.2014.06.013
DO - 10.1016/j.str.2014.06.013
M3 - Article
C2 - 25087510
AN - SCOPUS:84930188892
SN - 0969-2126
VL - 22
SP - 1252
EP - 1262
JO - Structure
JF - Structure
IS - 9
ER -
