Structural basis for signaling in the TNF and TNFR superfamilies
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LIGHT engages and signals through two TNFRSF members, HVEM and LTbetaR. Engagement of LIGHT with HVEM and LTbetaR regulates T cell proliferation, thymocyte differentiation, lymphocyte trafficking and migration after immunization. The biological signal initiated by LIGHT through HVEM or LTbetaR, can be modulated via direct competition with DcR3, a unique soluble member of the TNFRSF. In addition to LIGHT, DcR3 also neutralizes two other TNFSF members, FasL and TL1A, largely impeding formation of the FasL:Fas and TL1A:DR3 signaling assemblies. CD160 is a GPI-anchored receptor belonging to the IgSF, which engages MHC-I to enhance NK cell cytotoxicity. CD160 interacts with HVEM to either inhibit a subset of CD4+ T cell activities or augment the cytokine production and cytolytic function of NK cells.;Here I determined the structures of LIGHT, LIGHT:HVEM, LIGHT:DcR3, LIGHT mutants:DcR3, FasL:DcR3 and CD160. The crystal structure of LIGHT reveals a trimeric assembly of three identical monomers. Each protomer adopts a typical TNF ligand "jelly-roll" structure, which features two parallel beta-sheets forming the rigid scaffold supporting the flexible strand-connecting loops. The crystal structures of LIGHT:HVEM and LIGHT:DcR3 complexes suggest that the flexible loops of LIGHT are major determinants contributing to the recognition of HVEM and DcR3. Structures of DcR3 bound to its ligands provide models to investigate the residues contributing to the promiscuity of DcR3 (i.e., the ability to recognize three distinct TNF ligands). The crystal structures of the FasL:DcR3 and LIGHT:DcR3 complexes, along with the structure of TL1A:DcR3 complex previously determined by our lab reveal that all three ligands utilize the highly sequence diverse loops to interact with a similar surface on DcR3. This property allows us to design LIGHT mutants, which show biased binding affinities towards DcR3 and LTbetaR but not HVEM, and offer opportunities to further dissect the functions. The structure of CD160 shows a typical immunoglobulin organization. A cell-based alanine scan over the surface of CD160 indicates the possible residues contributing to the interaction with HVEM. SPR experiments reveal different affinities of CD160 binding with HVEM and MHC-I.