7lxc

Structural highlights

Disease

FADD_HUMAN Defects in FADD are the cause of infections recurrent associated with encephalopathy hepatic dysfunction and cardiovascular malformations (IEHDCM) [MIM:613759. A condition with biological features of autoimmune lymphoproliferative syndrome such as high-circulating CD4(-)CD8(-)TCR-alpha-beta(+) T-cell counts, and elevated IL10 and FASL levels. Affected individuals suffer from recurrent, stereotypical episodes of fever, encephalopathy, and mild liver dysfunction sometimes accompanied by generalized seizures. The episodes can be triggered by varicella zoster virus (VZV), measles mumps rubella (MMR) attenuated vaccine, parainfluenza virus, and Epstein-Barr virus (EBV).^[1]

Function

CFLAR_HUMAN Apoptosis regulator protein which may function as a crucial link between cell survival and cell death pathways in mammalian cells. Acts as an inhibitor of TNFRSF6 mediated apoptosis. A proteolytic fragment (p43) is likely retained in the death-inducing signaling complex (DISC) thereby blocking further recruitment and processing of caspase-8 at the complex. Full length and shorter isoforms have been shown either to induce apoptosis or to reduce TNFRSF-triggered apoptosis. Lacks enzymatic (caspase) activity.^[2] FADD_HUMAN Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation. Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis. Involved in interferon-mediated antiviral immune response, playing a role in the positive regulation of interferon signaling.^{[3] [4] [5] [6]}

References

1. ↑ Bolze A, Byun M, McDonald D, Morgan NV, Abhyankar A, Premkumar L, Puel A, Bacon CM, Rieux-Laucat F, Pang K, Britland A, Abel L, Cant A, Maher ER, Riedl SJ, Hambleton S, Casanova JL. Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet. 2010 Dec 10;87(6):873-81. doi: 10.1016/j.ajhg.2010.10.028. Epub, 2010 Nov 25. PMID:21109225 doi:10.1016/j.ajhg.2010.10.028
2. ↑ Scaffidi C, Schmitz I, Krammer PH, Peter ME. The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem. 1999 Jan 15;274(3):1541-8. PMID:9880531
3. ↑ Bolze A, Byun M, McDonald D, Morgan NV, Abhyankar A, Premkumar L, Puel A, Bacon CM, Rieux-Laucat F, Pang K, Britland A, Abel L, Cant A, Maher ER, Riedl SJ, Hambleton S, Casanova JL. Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet. 2010 Dec 10;87(6):873-81. doi: 10.1016/j.ajhg.2010.10.028. Epub, 2010 Nov 25. PMID:21109225 doi:10.1016/j.ajhg.2010.10.028
4. ↑ Carrington PE, Sandu C, Wei Y, Hill JM, Morisawa G, Huang T, Gavathiotis E, Wei Y, Werner MH. The structure of FADD and its mode of interaction with procaspase-8. Mol Cell. 2006 Jun 9;22(5):599-610. PMID:16762833 doi:10.1016/j.molcel.2006.04.018
5. ↑ Scott FL, Stec B, Pop C, Dobaczewska MK, Lee JJ, Monosov E, Robinson H, Salvesen GS, Schwarzenbacher R, Riedl SJ. The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature. 2009 Feb 19;457(7232):1019-22. Epub 2008 Dec 31. PMID:19118384 doi:nature07606
6. ↑ Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, Yin Q, Damko E, Jang SB, Raunser S, Robinson CV, Siegel RM, Walz T, Wu H. The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol. 2010 Nov;17(11):1324-9. Epub 2010 Oct 10. PMID:20935634 doi:10.1038/nsmb.1920
7. ↑ Panaitiu AE, Basiashvili T, Mierke DF, Pellegrini M. An engineered construct of cFLIP provides insight into DED1 structure and interactions. Structure. 2021 Nov 13. pii: S0969-2126(21)00379-8. doi:, 10.1016/j.str.2021.10.011. PMID:34800372 doi:http://dx.doi.org/10.1016/j.str.2021.10.011