LITAF (LPS-induced TNF-activating factor) (also known as SIMPLE; small integral membrane protein of the late endosome) is an endosome-associated integral membrane protein important for multivesicular body (MVB) sorting. It is a monotypic membrane protein with both termini exposed to the cytoplasm and is anchored to membranes via an in-plane helical membrane anchor, present within the highly conserved C-terminal region known as the 'LITAF domain' or 'SIMPLE-like domain'. The LITAF domain consists of conserved cysteines separated by a 22 residue hydrophobic region. LITAF domains are found throughout the eukaryotes, suggesting ancient conserved functions, with multiple instances of expansion, especially in the metazoa [ (PUBMED:27582497) (PUBMED:27927196) ].
The LITAF domain consists of five beta-sheets, three N-terminal and two C- terminal to the predicted hydrophobic anchor region and is stabilized by the coordination of a zinc atom by two pairs of evolutionarily conserved cysteine residues. Consistent with a protein domain that resides in close proximity to membranes, specific residues within the LITAF domain interact with phosphoethanolamine (PE) head groups. The anchoring-region of the LITAF domain is likely to embed into the cytosolic-facing monolayer of the membrane bilayer by adopting an amphipathic character [ (PUBMED:27927196) ].
Family alignment:
There are 3926 LITAF domains in 3906 proteins in SMART's nrdb database.
Click on the following links for more information.
Evolution (species in which this domain is found)
Taxonomic distribution of proteins containing LITAF domain.
This tree includes only several representative species. The complete taxonomic breakdown of all proteins with LITAF domain is also avaliable.
Click on the protein counts, or double click on taxonomic names to display all proteins containing LITAF domain in the selected taxonomic class.
Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
Identification of multiple proteins expressed in murine embryos as binding partners for the WW domains of the ubiquitin-protein ligase Nedd4.
Biochem J. 2000; 351: 557-65
Display abstract
Nedd4 is a member of a growing family of ubiquitin-protein ligases which consist of a lipid-binding domain, two to four WW domains and a C-terminal ubiquitin-protein ligase domain. The Nedd4 mRNA levels are developmentally regulated and Nedd4 protein is highly expressed in many mouse embryonic tissues. In this study we have used a far-Western screen to identify embryonic proteins that interact with the WW domains in mouse Nedd4. We report here identification of eight Nedd4 WW-domain-interacting proteins from mouse embryonic cDNA expression libraries. Two of the proteins are novel, while two have been identified previously as ligands for a WW domain. All of these proteins contain one or more PY motifs. In seven of the eight proteins, these PY motifs are necessary for their interaction with the WW domains of Nedd4. Using site-directed mutagenesis, and by using individual WW domains of Nedd4 as probes for far-Western analysis, we show that the three WW domains in Nedd4 interact with varying affinities with the PY motifs present in various Nedd4-binding proteins. These results provide evidence that Nedd4 can potentially interact with multiple proteins, possibly simultaneously, through its WW domains.
A novel lipopolysaccharide-induced transcription factor regulating tumornecrosis factor alpha gene expression: molecular cloning, sequencing,characterization, and chromosomal assignment.
Proc Natl Acad Sci U S A. 1999; 96: 4518-23
Display abstract
Lipopolysaccharide (LPS) is a potent stimulator of monocytes andmacrophages, causing secretion of tumor necrosis factor alpha (TNF-alpha)and other inflammatory mediators. Given the deleterious effects to thehost of TNF-alpha, it has been postulated that TNF-alpha gene expressionmust be tightly regulated. The nature of the nuclear factor(s) thatcontrol TNF-alpha gene transcription in humans remains obscure, althoughNF-kappaB has been suggested. Our previous studies pertaining tomacrophage response to LPS identified a novel DNA-binding domain locatedfrom -550 to -487 in the human TNF-alpha promoter that containstranscriptional activity, but lacks any known NF-kappaB-binding sites. Wehave used this DNA fragment to isolate and purify a 60-kDa protein bindingto this fragment and obtained its amino-terminal sequence, which was usedto design degenerate probes to screen a cDNA library from THP-1 cells. Anovel cDNA clone (1.8 kb) was isolated and fully sequenced.Characterization of this cDNA clone revealed that its induction wasdependent on LPS activation of THP-1 cells; hence, the name LPS-inducedTNF-alpha factor (LITAF). Inhibition of LITAF mRNA expression in THP-1cells resulted in a reduction of TNF-alpha transcripts. In addition, highlevel of expression of LITAF mRNA was observed predominantly in theplacenta, peripheral blood leukocytes, lymph nodes, and the spleen.Finally, chromosomal localization using fluorescence in situ hybridizationrevealed that LITAF mapped to chromosome 16p12-16p13.3. Together, thesefindings suggest that LITAF plays an important role in the activation ofthe human TNF-alpha gene and proposes a new mechanism to control TNF-alphagene expression.
Metabolism (metabolic pathways involving proteins which contain this domain)
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with LITAF domain which could be assigned to a KEGG orthologous group, and not all proteins containing LITAF domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
Links (links to other resources describing this domain)
