4mxw | pdb_00004mxw
Structure of heterotrimeric lymphotoxin LTa1b2 bound to lymphotoxin beta receptor LTbR and anti-LTa Fab
Structural highlights
FunctionTNR3_HUMAN Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT. Promotes apoptosis via TRAF3 and TRAF5. May play a role in the development of lymphoid organs.[1] [2] Publication Abstract from PubMedHomotrimeric TNF superfamily ligands signal by inducing trimers of their cognate receptors. As a biologically active heterotrimer, Lymphotoxin(LT)alpha1beta2 is unique in the TNF superfamily. How the three unique potential receptor-binding interfaces in LTalpha1beta2 trigger signaling via LTbeta Receptor (LTbetaR) resulting in lymphoid organogenesis and propagation of inflammatory signals is poorly understood. Here we show that LTalpha1beta2 possesses two binding sites for LTbetaR with distinct affinities and that dimerization of LTbetaR by LTalpha1beta2 is necessary and sufficient for signal transduction. The crystal structure of a complex formed by LTalpha1beta2, LTbetaR, and the fab fragment of an antibody that blocks LTbetaR activation reveals the lower affinity receptor-binding site. Mutations targeting each potential receptor-binding site in an engineered single-chain variant of LTalpha1beta2 reveal the high-affinity site. NF-kappaB reporter assays further validate that disruption of receptor interactions at either site is sufficient to prevent signaling via LTbetaR. Dimerization of LTbetaR by LTalpha1beta2 is necessary and sufficient for signal transduction.,Sudhamsu J, Yin J, Chiang EY, Starovasnik MA, Grogan JL, Hymowitz SG Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19896-901. doi:, 10.1073/pnas.1310838110. Epub 2013 Nov 18. PMID:24248355[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
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