Mechanistic basis for functional promiscuity in the TNF and TNF Receptor superfamilies: Structure of the light:DcR3 assembly

Weifeng Liu, Chenyang Zhan, Huiyong Cheng, P. Rajesh Kumar, Jeffrey B. Bonanno, Stanley G. Nathenson, Steven C. Almo

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1252-1262
Number of pages11
JournalStructure
Volume22
Issue number9
DOIs
StatePublished - Sep 2 2014

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ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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