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J. Biol. Chem., Vol. 280, Issue 24, 22741-22748, June 17, 2005

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Critical Assessment of Important Regions in the Subunit Association and Catalytic Action of the Severe Acute Respiratory Syndrome Coronavirus Main Protease^*

Wen-Chi Hsu, Hui-Chuan Chang, Chi-Yuan Chou, Pui-Jen Tsai, Pei-In Lin, and Gu-Gang Chang

From the Faculty of Life Sciences, Institute of Biochemistry, and Structural Biology Program, National Yang-Ming University, Taipei 112, Taiwan

The severe acute respiratory syndrome (SARS) coronavirus (CoV) main protease represents an attractive target for the development of novel anti-SARS agents. The tertiary structure of the protease consists of two distinct folds. One is the N-terminal chymotrypsin-like fold that consists of two structural domains and constitutes the catalytic machinery; the other is the C-terminal helical domain, which has an unclear function and is not found in other RNA virus main proteases. To understand the functional roles of the two structural parts of the SARS-CoV main protease, we generated the full-length of this enzyme as well as several terminally truncated forms, different from each other only by the number of amino acid residues at the C- or N-terminal regions. The quaternary structure and K_d value of the protease were analyzed by analytical ultracentrifugation. The results showed that the N-terminal 1–3 amino acid-truncated protease maintains 76% of enzyme activity and that the major form is a dimer, as in the wild type. However, the amino acids 1–4-truncated protease showed the major form to be a monomer and had little enzyme activity. As a result, the fourth amino acid seemed to have a powerful effect on the quaternary structure and activity of this protease. The last C-terminal helically truncated protease also exhibited a greater tendency to form monomer and showed little activity. We concluded that both the C- and the N-terminal regions influence the dimerization and enzyme activity of the SARS-CoV main protease.

Received for publication, March 8, 2005 , and in revised form, April 4, 2005.

^* This work was supported by the National Science Council, Republic of China. 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.

To whom correspondence should be addressed: Faculty of Life Sciences, National Yang-Ming University, 155 Li-Nong St., Section 2, Taipei 112, Taiwan. Tel.: 886-2-2820-1854; Fax: 886-2-2820-1886; E-mail: ggchang{at}ym.edu.tw.

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