Disease relevance of TEAD2

• Deficiencies in ETF or ETF-QO result in multiple acyl-CoA dehydrogenase deficiency, a human metabolic disease [1].
• We substituted a methionine for T244 in the alpha subunit of P. denitrificans ETF and expressed the mutant ETF in Escherichia coli [2].
• Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study [3].
• Oral mucositis was associated with poorer 'well being' at the start of PN compared with ETF (P < 0.0001), but this was reversed by the end of PN [4].
• Furthermore, PN was associated with more frequent exocrine pancreatic insufficiency than ETF (P = 0.001) [4].

High impact information on TEAD2

• First, electrons from the ETF flavin semiquinone may enter the ETF-QO flavin one by one, followed by rapid equilibration with the cluster [1].
• It catalyzes ubiquinone (UQ) reduction by ETF, linking oxidation of fatty acids and some amino acids to the mitochondrial respiratory chain [1].
• It lacked canonical TATA or CAAT boxes, but it contained several GC boxes with binding sites for the transcription factors SP1 and ETF [5].
• ETF binds to the promoter region, as measured by DNase I "footprinting" and gel-mobility-shift assays, and specifically stimulates the transcription of the EGFR gene in a reconstituted in vitro transcription system [6].
• These results suggest that ETF could play a role in the overexpression of the cellular oncogene EGFR [6].

Biological context of TEAD2

• Nuclear factor ETF specifically stimulates transcription from promoters without a TATA box [7].
• Here, we show that ETF recognizes various GC-rich sequences including stretches of deoxycytidine or deoxyguanosine residues and GC boxes with similar affinities [7].
• These studies indicate that a series of conformational changes occur during the assembly of the TMADH.ETF electron transfer complex and that the kinetics of assembly observed with mutant TMADH (Y442F/L/G) or ETF (alpha R237A) complexes are much slower than are the corresponding rates of electron transfer in these complexes [8].
• Overall molecular conformations as probed by small-angle x-ray scattering studies are indistinguishable for imprinted and non-imprinted ETF, suggesting that changes in structure likely involve confined reorganizations within the vicinity of the FAD [8].
• The mechanism of electron transfer between TMADH and ETF has been studied using stopped-flow kinetic and mutagenesis methods, and more recently by X-ray crystallography [9].

Anatomical context of TEAD2

• No CAT activity was observed when a 420-bp fragment lacking this GC box but containing the ETF-binding domains was similarly transfected into this cell line [10].
• Transfection with wild-type ETF alpha cDNA into cultured cells from both patients elevated incorporation of radioisotope-labelled fatty acids [11].
• Nutritional status and 'well-being' were compared prospectively in 39 children (mean age 8.1 years) who received nutritional support following bone marrow transplantion (BMT): 20 received enteral tube feeding (ETF; six received parenteral nutrition [PN] subsequently) and 19 with oral mucositis received PN (one received ETF subsequently) [4].
• The ferricenium assay is not as specific as the anaerobic ETF-linked assay in the biochemical diagnosis of medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts, and therefore is of limited clinical applicability in its present form [12].

Associations of TEAD2 with chemical compounds

• In this report, ETF, purified by using sequence-specific oligonucleotide affinity chromatography, is shown by renaturing material eluted from a NaDodSO4/polyacrylamide gel to be a protein with a molecular mass of 120 kDa [6].
• TMADH (trimethylamine dehydrogenase) is a complex iron-sulphur flavoprotein that forms a soluble electron-transfer complex with ETF (electron-transferring flavoprotein) [9].
• Inspection of the crystal structure of wild-type TMADH reveals that Tyr-442 is positioned along one side of a small cavity on the surface of the enzyme: Val 344, located at the bottom of this cavity, is the closest surface residue to the 4Fe-4S center of TMADH and is likely to be positioned on a major electron transfer pathway to ETF [13].
• This residue is highly conserved in the alpha subunits of all known ETFs, and the most frequent pathogenic mutation in human ETF encodes a methionine substitution at the corresponding position, alphaT266 [2].
• In contrast, mutation of Tyr-442 to Phe, Leu, Cys, and Gly leads to major reductions in the rate of electron transfer to ETF, but not to Fc(+) [14].

Analytical, diagnostic and therapeutic context of TEAD2

• The importance of these residues in electron transfer, both to ETF and to the artificial electron acceptor, ferricenium (Fc(+)), has been studied by site-directed mutagenesis and stopped-flow spectroscopy [14].
• No signal for ETF alpha was detected by immunoblotting in cases of missense mutants, while wild-type cDNA resulted in expression of ETF alpha protein [11].
• In conclusion, ultrafiltration of dialysate with the polysulfone ultrafilter ETF 609 leads to a potent reduction of cytokine-inducing activity [15].
• When immunoprecipitates were analyzed by SDS-PAGE, the mobilities of all the human acyl-CoA dehydrogenases and ETF subunits were identical to those of the rat counterparts with a single exception [16].

References