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J. Biol. Chem., Vol. 280, Issue 16, 16185-16196, April 22, 2005

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The ClpP Double Ring Tetradecameric Protease Exhibits Plastic Ring-Ring Interactions, and the N Termini of Its Subunits Form Flexible Loops That Are Essential for ClpXP and ClpAP Complex Formation^*

Anna Gribun¶, Matthew S. Kimber||**, Reagan Ching, Remco Sprangers, Klaus M. Fiebig||, and Walid A. Houry¶¶

From the Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8 and ^||Affinium Pharmaceuticals, Toronto, Ontario M5J 1V6, Canada

ClpP is a conserved serine-protease with two heptameric rings that enclose a large chamber containing the protease active sites. Each ClpP subunit can be divided into a handle region, which mediates ring-ring interactions, and a head domain. ClpP associates with the hexameric ATPases ClpX and ClpA, which can unfold and translocate substrate proteins through the ClpP axial pores into the protease lumen for degradation. We have determined the x-ray structure of Streptococcus pneumoniae ClpP(A153P) at 2.5 Å resolution. The structure revealed two novel features of ClpP which are essential for ClpXP and ClpAP functional activities. First, the Ala Pro mutation disrupts the handle region, resulting in an altered ring-ring dimerization interface, which, in conjunction with biochemical data, demonstrates the unusual plasticity of this region. Second, the structure shows the existence of a flexible N-terminal loop in each ClpP subunit. The loops line the axial pores in the ClpP tetradecamer and then protrude from the protease apical surface. The sequence of the N-terminal loop is highly conserved in ClpP across all kingdoms of life. These loops are essential determinants for complex formation between ClpP and ClpX/ClpA. Mutation of several amino acid residues in this loop or the truncation of the loop impairs ClpXP and ClpAP complex formation and prevents the coupling between ClpX/ClpA and ClpP activities.

Received for publication, December 15, 2004 , and in revised form, January 21, 2005.

^* This work was supported in part by a grant from the Canadian Institutes for Health Research (to W. A. H.). 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 1Y7O) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

These authors contributed equally to this work.

^¶ Postdoctoral fellow of the Canadian Institutes for Health Research; recipient of training program grant in protein folding: principles and diseases.

Recipient of a life sciences award from the University of Toronto.

Recipient of a European Molecular Biology Organization postdoctoral fellowship.

^** To whom correspondence may be addressed: Affinium Pharmaceuticals, 100 University Ave, North Tower, 12th floor, Toronto, Ontario M5J 1V6, Canada. E-mail: mkimber{at}afnm.com. ¶¶ Canadian Institutes of Health Research new investigator. To whom correspondence may be addressed: 1 King's College Circle, Medical Sciences Bldg., Dept. of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-946-7141; Fax: 416-978-8548; E-mail: walid.houry{at}utoronto.ca.

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