title: The functional readthrough extension of malate dehydrogenase reveals a modification of the genetic code.
abstract: Translational readthrough gives rise to C-terminally extended proteins, thereby providing the cell with new protein isoforms. These may have different properties from the parental proteins if the extensions contain functional domains. While for most genes amino acid incorporation at the stop codon is far lower than 0.1%, about 4% of malate dehydrogenase (MDH1) is physiologically extended by translational readthrough and the actual ratio of MDH1x (extended protein) to 'normal' MDH1 is dependent on the cell type. In human cells, arginine and tryptophan are co-encoded by the MDH1x UGA stop codon. Readthrough is controlled by the 7-nucleotide high-readthrough stop codon context without contribution of the subsequent 50 nucleotides encoding the extension. All vertebrate MDH1x is directed to peroxisomes via a hidden peroxisomal targeting signal (PTS) in the readthrough extension, which is more highly conserved than the extension of lactate dehydrogenase B. The hidden PTS of non-mammalian MDH1x evolved to be more efficient than the PTS of mammalian MDH1x. These results provide insight into the genetic and functional co-evolution of these dually localized dehydrogenases.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hofhuis
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Schueren
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Nötzel
authors.affiliation: Microarray and Deep Sequencing Core Facility, University Medical Center Göttingen, University of Göttingen, 37077 Göttingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lingner
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
authors.affiliation: Proteomics Group, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Jahn
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany sven.thoms@med.uni-goettingen.de.
authors.forename: Sven
authors.identifier: 0000-0003-3018-6363
authors.initials: S
authors.lastname: Thoms
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D002460:Cell Line; D018388:Codon, Terminator; D005815:Genetic Code; D006367:HeLa Cells; D006801:Humans; D008291:Malate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D020675:Peroxisomes / Q000235:genetics; D014176:Protein Biosynthesis; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D018388:Codon, Terminator; D014364:Tryptophan; D001120:Arginine; D008291:Malate Dehydrogenase
keywords: LDHBx; MDH1x; genetic code; peroxisome; redox shuttle; translational readthrough