Dataset Information

Mechanistic basis for functional promiscuity in the TNF and TNF receptor superfamilies: structure of the LIGHT:DcR3 assembly.

ABSTRACT: LIGHT initiates intracellular signaling via engagement of the two TNF receptors, HVEM and LT?R. 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 LT?R. 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.

SUBMITTER: Liu W

PROVIDER: S-EPMC4163024 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Mechanistic basis for functional promiscuity in the TNF and TNF receptor superfamilies: structure of the LIGHT:DcR3 assembly.

Liu Weifeng W Zhan Chenyang C Cheng Huiyong H Kumar P Rajesh PR Bonanno Jeffrey B JB Nathenson Stanley G SG Almo Steven C SC

Structure (London, England : 1993) 20140731 9

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 dise ...[more]

PMID: 25087510

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Project description:We present, to our knowledge, the first quantitative analysis of functional site diversity in homologous domain superfamilies. Different types of functional sites are considered separately. Our results show that most diverse superfamilies are very plastic in terms of the spatial location of their functional sites. This is especially true for protein-protein interfaces. In contrast, we confirm that catalytic sites typically occupy only a very small number of topological locations. Small-ligand binding sites are more diverse than expected, although in a more limited manner than protein-protein interfaces. In spite of the observed diversity, our results also confirm the previously reported preferential location of functional sites. We identify a subset of homologous domain superfamilies where diversity is particularly extreme, and discuss possible reasons for such plasticity, i.e. structural diversity. Our results do not contradict previous reports of preferential co-location of sites among homologues, but rather point at the importance of not ignoring other sites, especially in large and diverse superfamilies. Data on sites exploited by different relatives, within each well annotated domain superfamily, has been made accessible from the CATH website in order to highlight versatile superfamilies or superfamilies with highly preferential sites. This information is valuable for system biology and knowledge of any constraints on protein interactions could help in understanding the dynamic control of networks in which these proteins participate. The novelty of our work lies in the comprehensive nature of the analysis - we have used a significantly larger dataset than previous studies - and the fact that in many superfamilies we show that different parts of the domain surface are exploited by different relatives for ligand/protein interactions, particularly in superfamilies which are diverse in sequence and structure, an observation not previously reported on such a large scale. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.

Dataset Information

Mechanistic basis for functional promiscuity in the TNF and TNF receptor superfamilies: structure of the LIGHT:DcR3 assembly.

Publications

Mechanistic basis for functional promiscuity in the TNF and TNF receptor superfamilies: structure of the LIGHT:DcR3 assembly.

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