title: Peptide-N-glycanases and DNA repair proteins, Xp-C/Rad4, are, respectively, active and inactivated enzymes sharing a common transglutaminase fold.
abstract: Yeast RAD4, its human ortholog Xp-C and their orthologs in other eukaryotes are DNA repair proteins which participate in nucleotide excision repair through a ubiquitin-dependent process. However, no conserved globular domains that might have shed light on their origin or functions have been reported for these proteins. By using sequence profile analysis, we show that RAD4/Xp-C proteins contain the ancient transglutaminase fold and are specifically related to the recently characterized peptide-N-glycanases (PNGases) which remove glycans from glycoproteins during their degradation. The PNGases retain the catalytic triad that is typical of this fold and are predicted to have a reaction mechanism similar to that involved in transglutamination. In contrast, the RAD4/Xp-C proteins are predicted to be inactive and are likely to only possess the protein interaction function in DNA repair. These proteins also contain a long, low-complexity insert in the globular transglutaminase domain. The RAD4/Xp-C proteins, along with other inactive transglutaminase-fold proteins, represent a case of functional re-assignment of an ancient domain following the loss of the ancestral enzymatic activity.
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: V
authors.initials: V
authors.lastname: Anantharaman
authors.forename: E V
authors.initials: EV
authors.lastname: Koonin
authors.forename: L
authors.initials: L
authors.lastname: Aravind
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; D017510:Protein Folding; D029702:Schizosaccharomyces pombe Proteins; D017386:Sequence Homology, Amino Acid; D011503:Transglutaminases / Q000737:chemistry / Q000378:metabolism*; D015003:Yeasts / Q000201:enzymology
chemical_list: D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C082463:RAD4 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C086984:XPC protein, human; D011503:Transglutaminases; D000581:Amidohydrolases; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase