FAS-associated death domain protein (FADD)
The protein contains 208 amino acids for an estimated molecular weight of 23279 Da.
Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors (PubMed:7538907, PubMed:23955153, PubMed:19118384, PubMed:20935634, PubMed:16762833, PubMed:24025841). The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation (PubMed:7538907, PubMed:19118384, PubMed:20935634, PubMed:16762833). Active caspase-8 initiates the subsequent cascade of caspases mediating apoptosis (PubMed:16762833). Involved in interferon-mediated antiviral immune response, playing a role in the positive regulation of interferon signaling (PubMed:21109225). (updated: June 2, 2021)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology.
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| Variant | Description |
|---|---|
| IEHDCM |
Biological Process
Activation of cysteine-type endopeptidase activity
Activation of cysteine-type endopeptidase activity involved in apoptotic process
Activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway
Apoptotic process
Apoptotic signaling pathway
Behavioral response to cocaine
Cell surface receptor signaling pathway
Cellular response to mechanical stimulus
Death-inducing signaling complex assembly
Defense response to virus
Extrinsic apoptotic signaling pathway
Extrinsic apoptotic signaling pathway in absence of ligand
Extrinsic apoptotic signaling pathway via death domain receptors
Innate immune response
Kidney development
Lymph node development
Motor neuron apoptotic process
MyD88-independent toll-like receptor signaling pathway
Necroptotic signaling pathway
Negative regulation of activation-induced cell death of T cells
Negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
Negative regulation of necroptotic process
Positive regulation of activated T cell proliferation
Positive regulation of adaptive immune response
Positive regulation of apoptotic process
Positive regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation
Positive regulation of extrinsic apoptotic signaling pathway
Positive regulation of extrinsic apoptotic signaling pathway via death domain receptors
Positive regulation of I-kappaB kinase/NF-kappaB signaling
Positive regulation of interferon-gamma production
Positive regulation of interleukin-8 production
Positive regulation of macrophage differentiation
Positive regulation of proteolysis
Positive regulation of T cell mediated cytotoxicity
Positive regulation of transcription by RNA polymerase II
Positive regulation of tumor necrosis factor production
Positive regulation of type I interferon-mediated signaling pathway
Protein heterooligomerization
Regulation of extrinsic apoptotic signaling pathway in absence of ligand
Regulation of extrinsic apoptotic signaling pathway via death domain receptors
Regulation of tumor necrosis factor-mediated signaling pathway
Response to morphine
Spleen development
T cell differentiation in thymus
T cell homeostasis
Thymus development
Toll-like receptor 3 signaling pathway
Toll-like receptor 4 signaling pathway
Toll-like receptor signaling pathway
TRAIL-activated apoptotic signaling pathway
TRIF-dependent toll-like receptor signaling pathway
Viral process
Cellular Component
CD95 death-inducing signaling complex
Cell body
Cytoplasm
Cytosol
Death-inducing signaling complex
Membrane raft
Neuron projection
Nucleus
Plasma membrane
Ripoptosome
Molecular Function
Caspase binding
Death effector domain binding
Death receptor binding
Identical protein binding
Protease binding
Protein complex binding
Protein-containing complex binding
Receptor serine/threonine kinase binding
Tumor necrosis factor receptor binding
Tumor necrosis factor receptor superfamily binding
The reference OMIM entry for this protein is 602457
Fas-associated via death domain; fadd
Fas-associating protein with death domain
Mort1
DESCRIPTION
FADD is a universal adaptor protein in apoptosis that mediates signaling of all known death domain-containing members of the TNF receptor superfamily (Kabra et al., 2001).CLONING
Two cell surface cytokine receptors, FAS (134637) and the tumor necrosis factor (TNF) receptor (see TNFR1, 191190), trigger apoptosis by natural ligands or specific agonist antibodies. Both receptors contain a conserved intracellular death domain. Using a yeast 2-hybrid screen with the cytoplasmic domain of FAS as bait, Chinnaiyan et al. (1995) isolated FADD (FAS-associating protein with death domain) cDNAs. The predicted 208-amino acid protein contained a death domain that was 25 to 30% identical to those of FAS and TNFR1. FADD interacted with FAS both in vitro and in vivo.GENE STRUCTURE
Kim et al. (1996) reported that the FADD gene contains 2 exons and spans approximately 3.6 kb.MAPPING
By analysis of somatic cell hybrid panels and by fluorescence in situ hybridization, Kim et al. (1996) mapped the FADD gene to 11q13.3. They noted that this region is amplified in several human malignancies (see EMS1; 164765), and found that FADD, along with other genes on 11q13.3, was amplified in a breast cancer cell line.BIOCHEMICAL FEATURES
- Crystal Structure Scott et al. (2009) successfully formed and isolated the human FAS (134637)-FADD death domain complex and reported the 2.7-angstrom crystal structure. The complex shows a tetrameric arrangement of 4 FADD death domains bound to 4 FAS death domains. Scott et al. (2009) showed that an opening of the FAS death domain exposes the FADD binding site and simultaneously generates a FAS-FAS bridge. The result is a regulatory FAS-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental death-induced signaling complex (DISC) assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. Scott et al. (2009) concluded that, in addition to depicting a previously unknown mode of death domain interactions, their results further uncover a mechanism for receptor signaling solely by oligomerization and clustering events.GENE FUNCTION
Chinnaiyan et al. (1995) demonstrated that the in vivo interaction of FADD with FAS was due to the association of the respective death domains. Overexpression of FADD in mammalian cells induced apoptosis, which like FAS-induced apoptosis, was blocked by CrmA, a poxvirus gene product. Northern blot analysis revealed that FADD is expressed as a 1.6-kb mRNA in many fetal and adult tissues. The authors concluded that FADD may play an important role in the proximal signal transduction of FAS. Yeh et al. (1998) stated that the interaction of FADD and FAS through their C-terminal death domains unmasks the N-terminal effector domain of FADD, allowing it to recruit caspase-8 (CASP8; 601763) to the FAS signaling complex and thereby activating a cysteine protease cascade, leading to cell death. Balachandran et al. (2004) reported that mammalian cells lacking the death domain-containing protein FADD are defective in intracellular double-stranded RNA (dsRNA)-activated gene expression, including production of type I (alpha/beta) interferons (e.g., 147660), and are thus very susceptible to viral infection. The signaling pathway incorporating FADD is largely independent of Toll-like rece ... More on the omim web site
July 1, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 602457 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed