6zt0
From Proteopedia
Crystal structure of the Eiger TNF domain/Grindelwald extracellular domain complex
Structural highlights
FunctionEIGER_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:12065414, PubMed:12176339, 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 PubMedThe 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
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