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J. Biol. Chem., Vol. 279, Issue 48, 50060-50068, November 26, 2004

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Structure of the N-terminal Domain of PEX1 AAA-ATPase

CHARACTERIZATION OF A PUTATIVE ADAPTOR-BINDING DOMAIN^*

Kumiko Shiozawa, Nobuo Maita, Kentaro Tomii¶, Azusa Seto, Natsuko Goda, Yutaka Akiyama¶, Toshiyuki Shimizu, Masahiro Shirakawa, and Hidekazu Hiroaki||

From the Graduate School of Integrated Science, Yokohama City University, 1-7-29 Suehiro, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan, Japan Biological Informatics Consortium, Hatchobori, Chuo-ku, Tokyo, 104-0032, Japan, ^¶Computational Biology Research Center, The National Institute of Advanced Industrial Science and Technology, Aomi Frontier Building 2-43 Aomi, 17F, Koto-ku, Tokyo 135-0064, Japan

Peroxisomes are responsible for several pathways in primary metabolism, including -oxidation and lipid biosynthesis. PEX1 and PEX6 are hexameric AAA-type ATPases, both of which are indispensable in targeting over 50 peroxisomal resident proteins from the cytosol to the peroxisomes. Although the tandem AAA-ATPase domains in the central region of PEX1 and PEX6 are highly similar, the N-terminal sequences are unique. To better understand the distinct molecular function of these two proteins, we analyzed the unique N-terminal domain (NTD) of PEX1. Extensive computational analysis revealed weak similarity (<10% identity) of PEX1 NTD to the N-terminal domains of other membrane-related type II AAA-ATPases, such as VCP (p97) and NSF. We have determined the crystal structure of mouse PEX1 NTD at 2.05-Å resolution, which clearly demonstrated that the domain belongs to the double--barrel fold family found in the other AAA-ATPases. The N-domains of both VCP and NSF are structural neighbors of PEX1 NTD with a 2.7- and 2.1-Å root mean square deviation of backbone atoms, respectively. Our findings suggest that the supradomain architecture, which is composed of a single N-terminal domain followed by tandem AAA domains, is a common feature of organellar membrane-associating AAA-ATPases. We propose that PEX1 functions as a protein unfoldase in peroxisomal biogenesis, using its N-terminal putative adaptor-binding domain.

Received for publication, July 12, 2004 , and in revised form, August 12, 2004.

^* This work was supported by grants from the Japanese Ministry of Education, Science, Sports, and Culture (to M. S. and H. H.). This work was partly supported by grants from the Japan New Energy and Industrial Technology Development Organization (to N. M.). 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 atomic coordinates and structure factors (code 1wlf) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^|| To whom correspondence should be addressed. Tel.: 81-45-508-7214; Fax: 81-45-508-7361; E-mail: hiroakih{at}tsurumi.yokohama-cu.ac.jp.

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