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J. Biol. Chem., Vol. 281, Issue 19, 13751-13761, May 12, 2006

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Structure of the Mouse Peptide N-Glycanase-HR23 Complex Suggests Co-evolution of the Endoplasmic Reticulum-associated Degradation and DNA Repair Pathways^*

Gang Zhao, Xiaoke Zhou, Liqun Wang, Guangtao Li, Caroline Kisker^¶||, William J. Lennarz, and Hermann Schindelin^||1

From the Center for Structural Biology, Department of Biochemistry and Cell Biology, and ^¶Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794 and the ^||Rudolf Virchow Center for Experimental Biomedicine and Institute of Structural Biology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany

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.

Received for publication, January 5, 2006 , and in revised form, February 22, 2006.

The atomic coordinates and structure factors (codes 2F4M (Au-HR model) and 2F4O (Z-VAD inhibitor model)) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work has been supported by National Institutes of Health Grants GM70783 (to C. K.), GM33814 (to W. J. L.), and DK54835 (to H. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Center for Structural Biology, Stony Brook University, Stony Brook, NY 11794-5115. Tel.: 631-632-1022; Fax: 631-632-1555; E-mail: hermann.schindelin{at}sunysb.edu or hermann.schindelin{at}virchow.uni-wuerzburg.de.

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