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Originally published In Press as doi:10.1074/jbc.M210868200 on January 29, 2003

J. Biol. Chem., Vol. 278, Issue 15, 13333-13341, April 11, 2003
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Structural Basis of Calcification Inhibition by alpha 2-HS Glycoprotein/Fetuin-A
FORMATION OF COLLOIDAL CALCIPROTEIN PARTICLES*

Alexander HeissDagger , Alexander DuChesne§, Bernd DeneckeDagger , Joachim Grötzinger, Kazuhiko Yamamoto||, Thomas Renné**, and Willi Jahnen-DechentDagger Dagger Dagger

From Dagger  IZKF BIOMAT, University Clinics, RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany, § Max-Planck-Institute for Polymer Research, Ackermannweg 10, D-55128 Mainz, Germany,  Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany, || Department of Biochemistry, Kinki University School of Medicine, Osaka 589-8511, Japan, and ** Institute for Clinical Biochemistry and Pathobiochemistry, Josef-Schneider-Strasse 2, Julius-Maximilians-University, D-97080 Würzburg, Germany

Genetic evidence from mutant mice suggests that alpha 2-HS glycoprotein/fetuin-A (Ahsg) is a systemic inhibitor of precipitation of basic calcium phosphate preventing unwanted calcification. Using electron microscopy and dynamic light scattering, we demonstrate that precipitation inhibition by Ahsg is caused by the transient formation of soluble, colloidal spheres, containing Ahsg, calcium, and phosphate. These "calciprotein particles" of 30-150 nm in diameter are initially amorphous and soluble but turn progressively more crystalline and insoluble in a time- and temperature-dependent fashion. Solubilization in Ahsg-containing calciprotein particles provides a novel conceptual framework to explain how insoluble calcium precipitates may be transported and removed in the bodies of mammals. Mutational analysis showed that the basic calcium phosphate precipitation inhibition activity resides in the amino-terminal cystatin-like domain D1 of Ahsg. A structure-function analysis of wild type and mutant forms of cystatin-like domains from Ahsg, full-length fetuin-B, histidine-rich glycoprotein, and kininogen demonstrated that Ahsg domain D1 is most efficient in inhibiting basic calcium phosphate precipitation. The computer-modeled domain structures suggest that a dense array of acidic residues on an extended beta -sheet of the cystatin-like domain Ahsg-D1 mediates efficient inhibition.

* This work was supported by a grant from the Deutsche Forschungsgemeinschaft (to W. J-D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger To whom correspondence should be addressed: IZKF BIOMAT, University Clinics, Pauwelsstrasse 30, D-52074 Aachen, Germany. Tel.: 49-241-80-80163; Fax: 49-241-80-82573; E-mail: willi.jahnen@rwth-aachen.de.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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