title: Structure of the mouse peptide N-glycanase-HR23 complex suggests co-evolution of the endoplasmic reticulum-associated degradation and DNA repair pathways.
abstract: Peptide N-glycanase removes N-linked oligosaccharides from misfolded glycoproteins as part of the endoplasmic reticulum-associated degradation pathway. This process involves the formation of a tight complex of peptide N-glycanase with Rad23 in yeast and the orthologous HR23 proteins in mammals. In addition to its function in endoplasmic reticulum-associated degradation, HR23 is also involved in DNA repair, where it plays an important role in damage recognition in complex with the xeroderma pigmentosum group C protein. To characterize the dual role of HR23, we have determined the high resolution crystal structure of the mouse peptide N-glycanase catalytic core in complex with the xeroderma pigmentosum group C binding domain from HR23B. Peptide N-glycanase features a large cleft between its catalytic cysteine protease core and zinc binding domain. Opposite the zinc binding domain is the HR23B-interacting region, and surprisingly, the complex interface is fundamentally different from the orthologous yeast peptide N-glycanase-Rad23 complex. Different regions on both proteins are involved in complex formation, revealing an amazing degree of divergence in the interaction between two highly homologous proteins. Furthermore, the mouse peptide N-glycanase-HR23B complex mimics the interaction between xeroderma pigmentosum group C and HR23B, thereby providing a first structural model of how the two proteins interact within the nucleotide excision repair cascade in higher eukaryotes. The different interaction interfaces of the xeroderma pigmentosum group C binding domains in yeast and mammals suggest a co-evolution of the endoplasmic reticulum-associated degradation and DNA repair pathways.
authors.affiliation: Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794.
authors.forename: Liqun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794.
authors.forename: Guangtao
authors.initials: G
authors.lastname: Li
authors.affiliation: Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794; Rudolf Virchow Center for Experimental Biomedicine and Institute of Structural Biology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kisker
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794.
authors.forename: William J
authors.initials: WJ
authors.lastname: Lennarz
authors.affiliation: Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794; Rudolf Virchow Center for Experimental Biomedicine and Institute of Structural Biology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany. Electronic address: hermann.schindelin@sunysb.edu.
authors.forename: Hermann
authors.initials: H
authors.lastname: Schindelin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D019143:Evolution, Molecular; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011649:Pulmonary Alveolar Proteinosis; D015032:Zinc
chemical_list: D004268:DNA-Binding Proteins; C499250:Rad23b protein, mouse; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; D015032:Zinc