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J. Biol. Chem., Vol. 282, Issue 19, 14309-14315, May 11, 2007

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A Hydrophobic Pocket in the Active Site of Glycolytic Aldolase Mediates Interactions with Wiskott-Aldrich Syndrome Protein^*

Miguel St-Jean¹, Tina Izard, and Jurgen Sygusch²

From the Department of Biochemistry, University of Montreal, Montreal, Quebec H3C 3J7, Canada and Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Aldolase plays essential catalytic roles in glycolysis and gluconeogenesis. However, aldolase is a highly abundant protein that is remarkably promiscuous in its interactions with other cellular proteins. In particular, aldolase binds to highly acidic amino acid sequences, including the C terminus of the Wiskott-Aldrich syndrome protein, an actin nucleation-promoting factor. Here we report the crystal structure of tetrameric rabbit muscle aldolase in complex with a C-terminal peptide of Wiskott-Aldrich syndrome protein. Aldolase recognizes a short, four-residue DEWD motif (residues 498-501), which adopts a loose hairpin turn that folds around the central aromatic residue, enabling its tryptophan side chain to fit into a hydrophobic pocket in the active site of aldolase. The flanking acidic residues in this binding motif provide further interactions with conserved aldolase active site residues Arg-42 and Arg-303, aligning their side chains and forming the sides of the hydrophobic pocket. The binding of Wiskott-Aldrich syndrome protein to aldolase precludes intramolecular interactions of its C terminus with its active site and is competitive with substrate as well as with binding by actin and cortactin. Finally, based on this structure, a novel naphthol phosphate-based inhibitor of aldolase was identified, and its structure in complex with aldolase demonstrated mimicry of the Wiskott-Aldrich syndrome protein-aldolase interaction. The data support a model whereby aldolase exists in distinct forms that regulate glycolysis or actin dynamics.

Received for publication, December 15, 2006 , and in revised form, February 9, 2007.

The atomic coordinates and structure factors (code 2OT0 and 2OT1) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This research was supported by funding from the Natural Science and Engineering Research Council (Canada) and the Canadian Institutes for Health Research (to J. S.), and by a grant (GM071596) from the National Institutes of Health (to T. I.), a Cancer Center support grant, and by the American Lebanese Syrian Associated Charities. 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.

¹ Recipient of a Ph.D. scholarship from Fonds Québécois de la Recherche sur la Nature et les Technologies.

² To whom correspondence should be addressed: Biochimie/Médecine, Université de Montréal, CP 6128, Station Centre Ville, Montréal, Québec H3C 3J7, Canada. Tel.: 514-343-2389; Fax: 514-343-6463; E-mail: Jurgen.Sygusch{at}UMontreal.CA.

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