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J. Biol. Chem., Vol. 282, Issue 29, 21100-21109, July 20, 2007

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C1 Inhibitor Serpin Domain Structure Reveals the Likely Mechanism of Heparin Potentiation and Conformational Disease^*

László Beinrohr¹, Veronika Harmat^¶, József Dobó, Zsolt Lörincz, Péter Gál², and Péter Závodszky³

From the Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Karolina út 29, H-1113 Budapest, Hungary and the Protein Modeling Group and ^¶Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University, Hungarian Academy of Sciences, Pázmány Péter Sétány 1A, H-1117 Budapest, Hungary

C1 inhibitor, a member of the serpin family, is a major down-regulator of inflammatory processes in blood. Genetic deficiency of C1 inhibitor results in hereditary angioedema, a dominantly inheritable, potentially lethal disease. Here we report the first crystal structure of the serpin domain of human C1 inhibitor, representing a previously unreported latent form, which explains functional consequences of several naturally occurring mutations, two of which are discussed in detail. The presented structure displays a novel conformation with a seven-stranded -sheet A. The unique conformation of the C-terminal six residues suggests its potential role as a barrier in the active-latent transition. On the basis of surface charge pattern, heparin affinity measurements, and docking of a heparin disaccharide, a heparin binding site is proposed in the contact area of the serpin-proteinase encounter complex. We show how polyanions change the activity of the C1 inhibitor by a novel "sandwich" mechanism, explaining earlier reaction kinetic and mutagenesis studies. These results may help to improve therapeutic C1 inhibitor preparations used in the treatment of hereditary angioedema, organ transplant rejection, and heart attack.

Received for publication, January 29, 2007 , and in revised form, April 11, 2007.

The atomic coordinates and structure factors (code 2OAY) 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 by the European Community-Research Infrastructure Action under the FP6 "Structuring the European Research Area Programme" contract RII3-CT-2004–506008; Hungarian Ministry of Health Grant ETT; Hungarian National Science Foundation (OTKA) Grants T046444, T096912, D42199, and NI-61915; and the János Bolyai postdoctoral fellowship (to Z. L.). 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 Tables S1 and S2 and Figs. S1–S4.

¹ To whom correspondence may be addressed. Tel.: 36-1-209-3535; Fax: 36-1-466-5465; E-mail: lbeinrohr{at}enzim.hu. ² To whom correspondence may be addressed. Tel.: 36-1-209-3535; Fax: 36-1-466-5465; E-mail: gal{at}enzim.hu. ³ To whom correspondence may be addressed. Tel.: 36-1-209-3535; Fax: 36-1-466-5465; E-mail: zxp{at}enzim.hu.

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