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J. Biol. Chem., Vol. 282, Issue 40, 29594-29603, October 5, 2007

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Corticosteroid-binding Globulin, a Structural Basis for Steroid Transport and Proteinase-triggered Release^*

Michael A. Klieber, Caroline Underhill, Geoffrey L. Hammond¹, and Yves A. Muller²

From the Lehrstuhl für Biotechnik, Department of Biology, Friedrich-Alexander-University Erlangen-Nuremberg, D-91052 Erlangen, Germany and the Child and Family Research Institute and Department of Obstetrics & Gynaecology, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada

Corticosteroid-binding globulin (CBG) is a serine proteinase inhibitor (serpin) family member that transports glucocorticoids in blood and regulates their access to target cells. The 1.9Å crystal structure of rat CBG shows that its steroid-binding site resembles the thyroxin-binding site in the related serpin, thyroxin-binding globulin, and mutagenesis studies have confirmed the contributions of key residues that constitute the steroid-binding pocket. Unlike thyroxin-bound thyroxin-binding globulin, the cortisol-bound CBG displays an "active" serpin conformation with the proteinase-sensitive, reactive center loop (RCL) fully expelled from the regulatory -sheet A. Moreover, the CBG structure allows us to predict that complete insertion of the proteolytically cleaved RCL into the serpin fold occurs in concert with a displacement and unwinding of helix D that would disrupt the steroid-binding site. This allosteric coupling between RCL positioning and occupancy of the CBG steroid-binding site, which resembles the ligand (glycosamino-glycan)-dependent activation of the thrombin inhibitory serpins heparin cofactor II and anti-thrombin RCLs, ensures both optimal recognition of CBG by target proteinases and efficient release of steroid to sites of action.

Received for publication, June 18, 2007 , and in revised form, July 19, 2007.

The atomic coordinates and structure factors (code 2v6d) 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 Deutsche Forschungsgemeinschaft Grant Mu1477-5) and Canadian Institutes of Health Research Grant MOP 77586. 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Supported by a Tier 1 Canada Research Chair.

² To whom correspondence should be addressed: Henkestr. 91, D-91052 Erlangen, Germany. Tel.: 49-9131-8523082; Fax: 49-9131-8523080; E-mail: ymuller{at}biologie.uni-erlangen.de.

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