Advanced search
1 file | 4.64 MB

Defining the pathogenesis of the human Atp12p W94R mutation using a Saccharomyces cerevisiae yeast model

(2010) JOURNAL OF BIOLOGICAL CHEMISTRY. 285(6). p.4099-4109
Author
Organization
Abstract
Studies in yeast have shown that a deficiency in Atp12p prevents assembly of the extrinsic domain (F(1)) of complex V and renders cells unable to make ATP through oxidative phosphorylation. De Meirleir et al. (De Meirleir, L., Seneca, S., Lissens, W., De Clercq, I., Eyskens, F., Gerlo, E., Smet, J., and Van Coster, R. (2004) J. Med. Genet. 41, 120-124) have reported that a homozygous missense mutation in the gene for human Atp12p (HuAtp12p), which replaces Trp-94 with Arg, was linked to the death of a 14-month-old patient. We have investigated the impact of the pathogenic W94R mutation on Atp12p structure/function. Plasmid-borne wild type human Atp12p rescues the respiratory defect of a yeast ATP12 deletion mutant (Deltaatp12). The W94R mutation alters the protein at the most highly conserved position in the Pfam sequence and renders HuAtp12p insoluble in the background of Deltaatp12. In contrast, the yeast protein harboring the corresponding mutation, ScAtp12p(W103R), is soluble in the background of Deltaatp12 but not in the background of Deltaatp12Deltafmc1, a strain that also lacks Fmc1p. Fmc1p is a yeast mitochondrial protein not found in higher eukaryotes. Tryptophan 94 (human) or 103 (yeast) is located in a positively charged region of Atp12p, and hence its mutation to arginine does not alter significantly the electrostatic properties of the protein. Instead, we provide evidence that the primary effect of the substitution is on the dynamic properties of Atp12p.
Keywords
MOLECULAR-DYNAMICS, QUASI-NEWTON MATRICES, HYPERTROPHIC CARDIOMYOPATHY, MITOCHONDRIAL F-1-ATPASE, ESCHERICHIA-COLI, LEIGH-SYNDROME, ALPHA-SUBUNIT, F-1 ATPASE, SYNTHASE, PROTEINS

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 4.64 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Meulemans, Ann, Sara Seneca, Thomas Pribyl, Joél Smet, Valerie Alderweirldt, Anouk Waeytens, Willy Lissens, et al. 2010. “Defining the Pathogenesis of the Human Atp12p W94R Mutation Using a Saccharomyces Cerevisiae Yeast Model.” Journal of Biological Chemistry 285 (6): 4099–4109.
APA
Meulemans, A., Seneca, S., Pribyl, T., Smet, J., Alderweirldt, V., Waeytens, A., Lissens, W., et al. (2010). Defining the pathogenesis of the human Atp12p W94R mutation using a Saccharomyces cerevisiae yeast model. JOURNAL OF BIOLOGICAL CHEMISTRY, 285(6), 4099–4109.
Vancouver
1.
Meulemans A, Seneca S, Pribyl T, Smet J, Alderweirldt V, Waeytens A, et al. Defining the pathogenesis of the human Atp12p W94R mutation using a Saccharomyces cerevisiae yeast model. JOURNAL OF BIOLOGICAL CHEMISTRY. 2010;285(6):4099–109.
MLA
Meulemans, Ann, Sara Seneca, Thomas Pribyl, et al. “Defining the Pathogenesis of the Human Atp12p W94R Mutation Using a Saccharomyces Cerevisiae Yeast Model.” JOURNAL OF BIOLOGICAL CHEMISTRY 285.6 (2010): 4099–4109. Print.
@article{882699,
  abstract     = {Studies in yeast have shown that a deficiency in Atp12p prevents assembly of the extrinsic domain (F(1)) of complex V and renders cells unable to make ATP through oxidative phosphorylation. De Meirleir et al. (De Meirleir, L., Seneca, S., Lissens, W., De Clercq, I., Eyskens, F., Gerlo, E., Smet, J., and Van Coster, R. (2004) J. Med. Genet. 41, 120-124) have reported that a homozygous missense mutation in the gene for human Atp12p (HuAtp12p), which replaces Trp-94 with Arg, was linked to the death of a 14-month-old patient. We have investigated the impact of the pathogenic W94R mutation on Atp12p structure/function. Plasmid-borne wild type human Atp12p rescues the respiratory defect of a yeast ATP12 deletion mutant (Deltaatp12). The W94R mutation alters the protein at the most highly conserved position in the Pfam sequence and renders HuAtp12p insoluble in the background of Deltaatp12. In contrast, the yeast protein harboring the corresponding mutation, ScAtp12p(W103R), is soluble in the background of Deltaatp12 but not in the background of Deltaatp12Deltafmc1, a strain that also lacks Fmc1p. Fmc1p is a yeast mitochondrial protein not found in higher eukaryotes. Tryptophan 94 (human) or 103 (yeast) is located in a positively charged region of Atp12p, and hence its mutation to arginine does not alter significantly the electrostatic properties of the protein. Instead, we provide evidence that the primary effect of the substitution is on the dynamic properties of Atp12p.},
  author       = {Meulemans, Ann and Seneca, Sara and Pribyl, Thomas and Smet, Jo{\'e}l and Alderweirldt, Valerie and Waeytens, Anouk and Lissens, Willy and Van Coster, Rudy and De Meirleir, Linda and di Rago, Jean-Paul and Gatti, DomenicoL and Ackerman, Sharon H},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  language     = {eng},
  number       = {6},
  pages        = {4099--4109},
  title        = {Defining the pathogenesis of the human Atp12p W94R mutation using a Saccharomyces cerevisiae yeast model},
  url          = {http://dx.doi.org/10.1074/jbc.M109.046920},
  volume       = {285},
  year         = {2010},
}

Altmetric
View in Altmetric
Web of Science
Times cited: