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LAT1  -  dihydrolipoyllysine-residue acetyltransferase

Saccharomyces cerevisiae S288c

Synonyms: Dihydrolipoamide acetyltransferase component of pyruvate dehydrogenase complex, Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial, N2374, ODP2, PDA2, ...
 
 
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Disease relevance of LAT1

  • A cDNA was isolated from rat C6 glioma cells by expression cloning which encodes a novel Na+-independent neutral amino acid transporter designated LAT1 [1].
  • The E2 core of the complex is arranged to form a pentagonal dodecahedron, as shown by electron microscopic images, resembling the quaternary structures of PDH complexes from gram-positive bacteria and eukaryotes [2].
  • In addition we also report the in vivo modification of lipoamide present in the above-mentioned E2 subunits under the stressing conditions tested and that this also occurs with the homologous enzymes present in Escherichia coli cells that were used for comparative analysis [3].
  • Functional analysis of the papilloma virus E2 trans-activator in Saccharomyces cerevisiae [4].
  • Significantly, the interaction between Ubc4 and the proteasome is strongly induced by heat stress, consistent with the requirement for this E2 for efficient stress tolerance [5].
 

High impact information on LAT1

  • Amino acids necessary for DNA contact and dimerization imply novel motifs in the papillomavirus E2 trans-activator [6].
  • No heterodimeric complexes were formed when pools of E2 of varying lengths were mixed, and only proteins with tryptophan at position 360 could be UV cross-linked [6].
  • The level of trans-activation was dependent on the position of the E2 DNA-binding sites in relation to the yeast promoter, with the maximal effect demonstrated when the binding sites were positioned upstream [4].
  • Reconstitution of papillomavirus E2-mediated plasmid maintenance in Saccharomyces cerevisiae by the Brd4 bromodomain protein [7].
  • Using a panel of mutated E2 proteins, we determined that plasmid stability required the ability of E2 to bind DNA and to interact with Brd4 and mammalian mitotic chromosomes but did not require its replication initiation and transactivation functions [7].
 

Biological context of LAT1

  • Mutant cells transformed with LAT1 on a unit-copy plasmid produced a PDH complex very similar to that of the wild-type PDH complex [8].
  • LAT1 exhibits relatively low but significant amino acid sequence similarity to mammalian cationic amino acid transporters and amino acid permeases of bacteria and yeasts, indicating LAT1 is a new member of the APC superfamily [1].
  • Because of highly regulated nature and high level of expression in tumor cell lines, LAT1 is thought to be up-regulated to support the high protein synthesis for cell growth and cell activation [1].
  • Dihydrolipoamide acyltransferase (E2), a catalytic and structural component of the three functional classes of multienzyme complexes that catalyze the oxidative decarboxylation of alpha-keto acids, forms the central core to which the other components attach [9].
  • To gain further insight into the number and localization of binding sites for E3BP on the 60-mer E2, truncated forms of the E3BP lacking the lipoyl and E3-binding domains were engineered by deletion mutagenesis [10].
 

Associations of LAT1 with chemical compounds

  • Like the lipoamide-containing forms of Kgd2, Lat1, and Gcv3, this protein also showed decreased lipoic acid reactivity in the nfs1-14 mutant [11].
  • Replacement of both lysine-47 in E2 and the equivalent lysine-43 in protein X by arginine resulted in complete loss of overall activity of the mutant PDH complex.(ABSTRACT TRUNCATED AT 250 WORDS)[8]
  • Analysis of subunit composition revealed a PDH (E1) consisting of the two subunits E1alpha (38 kDa) and E1beta (56 kDa), a dihydrolipoamide acetyltransferase (E2) of 48 kDa, and a lipoamide dehydrogenase (E3) of 50 kDa [2].
  • Gel chromatography in the presence of 6 M guanidine . HCl gave a value of 52 000 for E2 indicating anomalous electrophoretic migration as described for the E2 components of other pyruvate dehydrogenase complexes [12].
  • E2 was isolated by gel filtration of the complex in the presence of 2 M KBr, and E3 was obtained by hydroxyapatite chromatography in 8 M urea [12].
 

Physical interactions of LAT1

  • The results showed that the E1-E2 subcomplex binds about 12 E3BP monomers attached to 12 E3 homodimers [13].
 

Other interactions of LAT1

  • Mixtures containing tE2 or E1-E2 subcomplex and excess E3BP or E3BP-E3 complex were subjected to ultracentrifugation to separate the large complexes from unbound E3BP or E3BP-E3, and the complexes were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis [13].
 

Analytical, diagnostic and therapeutic context of LAT1

  • Peptide mapping of irradiated E2 protein localized the cross-link to an 18-amino-acid region bracketing this tryptophan [6].
  • We report the results of applying a new computational method, quantized elastic deformational model, to simulating the conformational fluctuations of the truncated E2 core, using low-resolution electron cryomicroscopy density maps [14].
  • The C-terminal 266 amino acids of BPV1 E1 (E1C266) interacted strongly with E2 in the yeast system and in a mammalian two-hybrid assay [15].

References

  1. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). Kanai, Y., Segawa, H., Miyamoto, K., Uchino, H., Takeda, E., Endou, H. J. Biol. Chem. (1998) [Pubmed]
  2. Purification of the pyruvate dehydrogenase multienzyme complex of Zymomonas mobilis and identification and sequence analysis of the corresponding genes. Neveling, U., Klasen, R., Bringer-Meyer, S., Sahm, H. J. Bacteriol. (1998) [Pubmed]
  3. Oxidative stress promotes specific protein damage in Saccharomyces cerevisiae. Cabiscol, E., Piulats, E., Echave, P., Herrero, E., Ros, J. J. Biol. Chem. (2000) [Pubmed]
  4. Functional analysis of the papilloma virus E2 trans-activator in Saccharomyces cerevisiae. Lambert, P.F., Dostatni, N., McBride, A.A., Yaniv, M., Howley, P.M., Arcangioli, B. Genes Dev. (1989) [Pubmed]
  5. Evidence for an interaction between ubiquitin-conjugating enzymes and the 26S proteasome. Tongaonkar, P., Chen, L., Lambertson, D., Ko, B., Madura, K. Mol. Cell. Biol. (2000) [Pubmed]
  6. Amino acids necessary for DNA contact and dimerization imply novel motifs in the papillomavirus E2 trans-activator. Prakash, S.S., Grossman, S.R., Pepinsky, R.B., Laimins, L.A., Androphy, E.J. Genes Dev. (1992) [Pubmed]
  7. Reconstitution of papillomavirus E2-mediated plasmid maintenance in Saccharomyces cerevisiae by the Brd4 bromodomain protein. Brannon, A.R., Maresca, J.A., Boeke, J.D., Basrai, M.A., McBride, A.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  8. Functional analysis of the domains of dihydrolipoamide acetyltransferase from Saccharomyces cerevisiae. Lawson, J.E., Niu, X.D., Reed, L.J. Biochemistry (1991) [Pubmed]
  9. On the unique structural organization of the Saccharomyces cerevisiae pyruvate dehydrogenase complex. Stoops, J.K., Cheng, R.H., Yazdi, M.A., Maeng, C.Y., Schroeter, J.P., Klueppelberg, U., Kolodziej, S.J., Baker, T.S., Reed, L.J. J. Biol. Chem. (1997) [Pubmed]
  10. Stoichiometry of binding of mature and truncated forms of the dihydrolipoamide dehydrogenase-binding protein to the dihydrolipoamide acetyltransferase core of the pyruvate dehydrogenase complex from Saccharomyces cerevisiae. Maeng, C.Y., Yazdi, M.A., Reed, L.J. Biochemistry (1996) [Pubmed]
  11. Modifications of the lipoamide-containing mitochondrial subproteome in a yeast mutant defective in cysteine desulfurase. Onder, O., Yoon, H., Naumann, B., Hippler, M., Dancis, A., Daldal, F. Mol. Cell Proteomics (2006) [Pubmed]
  12. Pyruvate dehydrogenase complex from baker's yeast. 2. Molecular structure, dissociation, and implications for the origin of mitochondria. Kresze, G.B., Ronft, H. Eur. J. Biochem. (1981) [Pubmed]
  13. Expression, purification, and characterization of the dihydrolipoamide dehydrogenase-binding protein of the pyruvate dehydrogenase complex from Saccharomyces cerevisiae. Maeng, C.Y., Yazdi, M.A., Niu, X.D., Lee, H.Y., Reed, L.J. Biochemistry (1994) [Pubmed]
  14. Conformational flexibility of pyruvate dehydrogenase complexes: a computational analysis by quantized elastic deformational model. Kong, Y., Ming, D., Wu, Y., Stoops, J.K., Zhou, Z.H., Ma, J. J. Mol. Biol. (2003) [Pubmed]
  15. Two distinct regions of the BPV1 E1 replication protein interact with the activation domain of E2. Moscufo, N., Sverdrup, F., Breiding, D.E., Androphy, E.J. Virus Res. (1999) [Pubmed]
 
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