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J. Biol. Chem., Vol. 280, Issue 23, 22356-22364, June 10, 2005

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The High Resolution Crystal Structure of the Human Tumor Suppressor Maspin Reveals a Novel Conformational Switch in the G-helix^*

From the ^aThe Protein Crystallography Unit, Monash Centre for Synchrotron Science and The Department of Biochemistry and Molecular Biology; School of Biomedical Sciences, Faculty of Medicine, Monash University, Clayton, Victoria 3800, Australia, the ^bVictorian Bioinformatics Consortium, P. O. Box 53, Monash University, Clayton, Victoria, 3800, Australia, ^cARC Centre for Structural and Functional Microbial Genomics, Monash University, Clayton, Victoria 3800, Australia, and the ^fConway Institute, University College Dublin, Dublin, Ireland

Maspin is a serpin that acts as a tumor suppressor in a range of human cancers, including tumors of the breast and lung. Maspin is crucial for development, because homozygous loss of the gene is lethal; however, the precise physiological role of the molecule is unclear. To gain insight into the function of human maspin, we have determined its crystal structure in two similar, but non-isomorphous crystal forms, to 2.1- and 2.8-Å resolution, respectively. The structure reveals that maspin adopts the native serpin fold in which the reactive center loop is expelled fully from the A -sheet, makes minimal contacts with the core of the molecule, and exhibits a high degree of flexibility. A buried salt bridge unique to maspin orthologues causes an unusual bulge in the region around the D and E -helices, an area of the molecule demonstrated in other serpins to be important for cofactor recognition. Strikingly, the structural data reveal that maspin is able to undergo conformational change in and around the G -helix, switching between an open and a closed form. This change dictates the electrostatic character of a putative cofactor binding surface and highlights this region as a likely determinant of maspin function. The high resolution crystal structure of maspin provides a detailed molecular framework to elucidate the mechanism of function of this important tumor suppressor.

Received for publication, October 25, 2004 , and in revised form, March 8, 2005.

The atomic coordinates and structure factors (codes 1XU8 and 1WZ9) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by the National Health and Medical Research Council of Australia (NHMRC), the Australian Research Council, and the state government of Victoria (Australia). 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.

^d These authors contributed equally to this work.

^e An Anti Cancer of Victoria Research Fellow and Monash University Research Fellow.

^g A Monash University Logan Fellow and R. D. Wright Fellow of the NHRMC.

^h Supported by a Wellcome Trust Senior Research Fellowship in Biomedical Science in Australia.

ⁱ Joint senior authors.

^j To whom correspondence may be addressed: Tel.: 613-9405-3736; Fax: 613-9905-4699; E-mail: Jamie.Rossjohn{at}med.monash.edu.au. ^k To whom correspondence may be addressed: Tel.: 613-9905-3747; Fax: 613-9905-4699; E-mail: James.Whisstock{at}med.monash.edu.au.

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