|4mxw, resolution 3.60Å ()|
|Gene:||LTBR, D12S370, TNFCR, TNFR3, TNFRSF3 (HUMAN), LTA, TNFB, TNFSF1 (HUMAN), LTB, TNFC, TNFSF3 (HUMAN)|
Structure of heterotrimeric lymphotoxin LTa1b2 bound to lymphotoxin beta receptor LTbR and anti-LTa Fab
Homotrimeric 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
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[TNFB_HUMAN] Genetic variations in LTA are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:607507]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis).
[TNR3_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.  [TNFC_HUMAN] Cytokine that binds to LTBR/TNFRSF3. May play a specific role in immune response regulation. Provides the membrane anchor for the attachment of the heterotrimeric complex to the cell surface. Isoform 2 is probably non-functional. [TNFB_HUMAN] Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM. In its heterotrimeric form with LTB binds to TNFRSF3/LTBR. Lymphotoxin is produced by lymphocytes and cytotoxic for a wide range of tumor cells in vitro and in vivo.
About this Structure
- Sudhamsu J, Yin J, Chiang EY, Starovasnik MA, Grogan JL, Hymowitz SG. Dimerization of LTbetaR by LTalpha1beta2 is necessary and sufficient for signal transduction. 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 doi:http://dx.doi.org/10.1073/pnas.1310838110
- ↑ Crowe PD, VanArsdale TL, Walter BN, Ware CF, Hession C, Ehrenfels B, Browning JL, Din WS, Goodwin RG, Smith CA. A lymphotoxin-beta-specific receptor. Science. 1994 Apr 29;264(5159):707-10. PMID:8171323
- ↑ Rooney IA, Butrovich KD, Glass AA, Borboroglu S, Benedict CA, Whitbeck JC, Cohen GH, Eisenberg RJ, Ware CF. The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J Biol Chem. 2000 May 12;275(19):14307-15. PMID:10799510