6zt0 | pdb_00006zt0

Crystal structure of the Eiger TNF domain/Grindelwald extracellular domain complex

Structural highlights

6zt0 is a 2 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.02Å
Ligands:	EDO
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

EIGER_DROME Cytokine which acts as a ligand for wgn (PubMed:12894227). Also acts as a ligand for grnd (PubMed:25874673). Induces apoptosis by triggering JNK signaling (PubMed:12176339, PubMed:12065414, PubMed:12894227). Required for JNK-dependent non-autonomous apoptosis through release from apoptotic cells and activation of apoptosis in neighboring cells (PubMed:24066226). Required for JNK-independent damage-induced apoptosis in the embryonic central nervous system through regulation of the pro-apoptotic gene hid (PubMed:25754009). Involved in the innate immune response to extracellular pathogens (PubMed:17381241). Plays a role in the melanization immune response through its involvement in the rupture of crystal cells and subsequent release of prophenoloxidase (PubMed:17356067). Following UV-induced epidermal damage, released from apoptotic epidermal cells, binds to the wgn receptor on nociceptive sensory neurons and plays a role in development of thermal allodynia, a responsiveness to subthreshold thermal stimuli which are not normally perceived as noxious (PubMed:19375319). Involved in glial cell division induced by neuronal programmed cell death and injury (PubMed:19019992). Has tumor suppressor activity and eliminates oncogenic cells from epithelia, thereby maintaining epithelial integrity (PubMed:19289090).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11]

Publication Abstract from PubMed

The Drosophila tumour necrosis factor (TNF) ligand-receptor system consists of a unique ligand, Eiger (Egr), and two receptors, Grindelwald (Grnd) and Wengen (Wgn), and therefore provides a simple system for exploring the interplay between ligand and receptors, and the requirement for Grnd and Wgn in TNF/Egr-mediated processes. Here, we report the crystallographic structure of the extracellular domain (ECD) of Grnd in complex with Egr, a high-affinity hetero-hexameric assembly reminiscent of human TNF:TNFR complexes. We show that ectopic expression of Egr results in internalisation of Egr:Grnd complexes in vesicles, a step preceding and strictly required for Egr-induced apoptosis. We further demonstrate that Wgn binds Egr with much reduced affinity and is localised in intracellular vesicles that are distinct from those containing Egr:Grnd complexes. Altogether, our data provide insight into ligand-mediated activation of Grnd and suggest that distinct affinities of TNF ligands for their receptors promote different and non-redundant cellular functions.

Drosophila TNFRs Grindelwald and Wengen bind Eiger with different affinities and promote distinct cellular functions.,Palmerini V, Monzani S, Laurichesse Q, Loudhaief R, Mari S, Cecatiello V, Olieric V, Pasqualato S, Colombani J, Andersen DS, Mapelli M Nat Commun. 2021 Apr 6;12(1):2070. doi: 10.1038/s41467-021-22080-9. PMID:33824334^[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Igaki T, Kanda H, Yamamoto-Goto Y, Kanuka H, Kuranaga E, Aigaki T, Miura M. Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. EMBO J. 2002 Jun 17;21(12):3009-18. PMID:12065414 doi:10.1093/emboj/cdf306
↑ Moreno E, Yan M, Basler K. Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr Biol. 2002 Jul 23;12(14):1263-8. PMID:12176339 doi:10.1016/s0960-9822(02)00954-5
↑ Kauppila S, Maaty WS, Chen P, Tomar RS, Eby MT, Chapo J, Chew S, Rathore N, Zachariah S, Sinha SK, Abrams JM, Chaudhary PM. Eiger and its receptor, Wengen, comprise a TNF-like system in Drosophila. Oncogene. 2003 Jul 31;22(31):4860-7. PMID:12894227 doi:10.1038/sj.onc.1206715
↑ Bidla G, Dushay MS, Theopold U. Crystal cell rupture after injury in Drosophila requires the JNK pathway, small GTPases and the TNF homolog Eiger. J Cell Sci. 2007 Apr 1;120(Pt 7):1209-15. PMID:17356067 doi:10.1242/jcs.03420
↑ Schneider DS, Ayres JS, Brandt SM, Costa A, Dionne MS, Gordon MD, Mabery EM, Moule MG, Pham LN, Shirasu-Hiza MM. Drosophila eiger mutants are sensitive to extracellular pathogens. PLoS Pathog. 2007 Mar;3(3):e41. PMID:17381241 doi:10.1371/journal.ppat.0030041
↑ Kato K, Awasaki T, Ito K. Neuronal programmed cell death induces glial cell division in the adult Drosophila brain. Development. 2009 Jan;136(1):51-9. PMID:19019992 doi:10.1242/dev.023366
↑ Igaki T, Pastor-Pareja JC, Aonuma H, Miura M, Xu T. Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev Cell. 2009 Mar;16(3):458-65. PMID:19289090 doi:10.1016/j.devcel.2009.01.002
↑ Babcock DT, Landry C, Galko MJ. Cytokine signaling mediates UV-induced nociceptive sensitization in Drosophila larvae. Curr Biol. 2009 May 26;19(10):799-806. PMID:19375319 doi:10.1016/j.cub.2009.03.062
↑ Pérez-Garijo A, Fuchs Y, Steller H. Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway. Elife. 2013 Sep 24;2:e01004. PMID:24066226 doi:10.7554/eLife.01004
↑ Shklover J, Levy-Adam F, Kurant E. The role of Drosophila TNF Eiger in developmental and damage-induced neuronal apoptosis. FEBS Lett. 2015 Apr 2;589(8):871-9. PMID:25754009 doi:10.1016/j.febslet.2015.02.032
↑ Andersen DS, Colombani J, Palmerini V, Chakrabandhu K, Boone E, Rothlisberger M, Toggweiler J, Basler K, Mapelli M, Hueber AO, Leopold P. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature. 2015 Jun 25;522(7557):482-6. doi: 10.1038/nature14298. Epub 2015 Apr 15. PMID:25874673 doi:https://dx.doi.org/10.1038/nature14298
↑ Palmerini V, Monzani S, Laurichesse Q, Loudhaief R, Mari S, Cecatiello V, Olieric V, Pasqualato S, Colombani J, Andersen DS, Mapelli M. Drosophila TNFRs Grindelwald and Wengen bind Eiger with different affinities and promote distinct cellular functions. Nat Commun. 2021 Apr 6;12(1):2070. doi: 10.1038/s41467-021-22080-9. PMID:33824334 doi:https://dx.doi.org/10.1038/s41467-021-22080-9

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OCA

[1] Igaki T, Kanda H, Yamamoto-Goto Y, Kanuka H, Kuranaga E, Aigaki T, Miura M. Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. EMBO J. 2002 Jun 17;21(12):3009-18. PMID:12065414 doi:10.1093/emboj/cdf306

[2] Moreno E, Yan M, Basler K. Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr Biol. 2002 Jul 23;12(14):1263-8. PMID:12176339 doi:10.1016/s0960-9822(02)00954-5

[3] Kauppila S, Maaty WS, Chen P, Tomar RS, Eby MT, Chapo J, Chew S, Rathore N, Zachariah S, Sinha SK, Abrams JM, Chaudhary PM. Eiger and its receptor, Wengen, comprise a TNF-like system in Drosophila. Oncogene. 2003 Jul 31;22(31):4860-7. PMID:12894227 doi:10.1038/sj.onc.1206715

[4] Bidla G, Dushay MS, Theopold U. Crystal cell rupture after injury in Drosophila requires the JNK pathway, small GTPases and the TNF homolog Eiger. J Cell Sci. 2007 Apr 1;120(Pt 7):1209-15. PMID:17356067 doi:10.1242/jcs.03420

[5] Schneider DS, Ayres JS, Brandt SM, Costa A, Dionne MS, Gordon MD, Mabery EM, Moule MG, Pham LN, Shirasu-Hiza MM. Drosophila eiger mutants are sensitive to extracellular pathogens. PLoS Pathog. 2007 Mar;3(3):e41. PMID:17381241 doi:10.1371/journal.ppat.0030041

[6] Kato K, Awasaki T, Ito K. Neuronal programmed cell death induces glial cell division in the adult Drosophila brain. Development. 2009 Jan;136(1):51-9. PMID:19019992 doi:10.1242/dev.023366

[7] Igaki T, Pastor-Pareja JC, Aonuma H, Miura M, Xu T. Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. Dev Cell. 2009 Mar;16(3):458-65. PMID:19289090 doi:10.1016/j.devcel.2009.01.002

[8] Babcock DT, Landry C, Galko MJ. Cytokine signaling mediates UV-induced nociceptive sensitization in Drosophila larvae. Curr Biol. 2009 May 26;19(10):799-806. PMID:19375319 doi:10.1016/j.cub.2009.03.062

[9] Pérez-Garijo A, Fuchs Y, Steller H. Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway. Elife. 2013 Sep 24;2:e01004. PMID:24066226 doi:10.7554/eLife.01004

[10] Shklover J, Levy-Adam F, Kurant E. The role of Drosophila TNF Eiger in developmental and damage-induced neuronal apoptosis. FEBS Lett. 2015 Apr 2;589(8):871-9. PMID:25754009 doi:10.1016/j.febslet.2015.02.032

[11] Andersen DS, Colombani J, Palmerini V, Chakrabandhu K, Boone E, Rothlisberger M, Toggweiler J, Basler K, Mapelli M, Hueber AO, Leopold P. The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature. 2015 Jun 25;522(7557):482-6. doi: 10.1038/nature14298. Epub 2015 Apr 15. PMID:25874673 doi:https://dx.doi.org/10.1038/nature14298

[12] Palmerini V, Monzani S, Laurichesse Q, Loudhaief R, Mari S, Cecatiello V, Olieric V, Pasqualato S, Colombani J, Andersen DS, Mapelli M. Drosophila TNFRs Grindelwald and Wengen bind Eiger with different affinities and promote distinct cellular functions. Nat Commun. 2021 Apr 6;12(1):2070. doi: 10.1038/s41467-021-22080-9. PMID:33824334 doi:https://dx.doi.org/10.1038/s41467-021-22080-9

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6zt0 | pdb_00006zt0

Crystal structure of the Eiger TNF domain/Grindelwald extracellular domain complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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