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J. Biol. Chem., Vol. 279, Issue 13, 12102-12109, March 26, 2004
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From the
Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht and the ||Department of Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3485 CX Utrecht, The Netherlands and ¶INSERM U143, 84 Rue Général Leclerc, 94276 Le Kremlin-Bicêtre, France
To explore the molecular basis of von Willebrand factor (VWF) clearance, an experimental model employing VWF-deficient mice was developed. Biodistribution was examined by the injection of radiolabeled VWF, which was primarily directed to the liver with minor amounts in other organs. Disappearance of VWF from plasma was characterized by a rapid initial phase (t
= 13 min) and a slow secondary phase (t
= 3 h), with a mean residence time (MRT) of 2.8 h. A similar clearance was observed for VWF consisting of only high or low molecular weight multimers, indicating that, in our experimental model, clearance is independent of multimeric distribution. This allowed us to compare the survival of full-length VWF to truncated variants. Deletion of both the amino-terminal D'-D3 and carboxyl-terminal D4-CK domains resulted in a fragment with a similar clearance to wild-type VWF. Deletion of only the D'-D3 region was associated with an almost 2-fold lower recovery and increased clearance (MRT = 1.6 h), whereas deletion of only the D4-CK region resulted in a significantly reduced clearance (MRT = 4.5 h, p < 0.02). These results point to a role of the D'-D3 region in preventing clearance of VWF. Furthermore, replacement of D3 domain residue Arg-1205 by His resulted in a markedly increased clearance (MRT = 0.3 h; p = 0.004). Therefore, this mutation seems to abrogate the protective effect of the D'-D3 region. In vitro analysis of this mutant also revealed a 2-fold reduced affinity for VWF propeptide at low pH, showing that mutation of Arg-1205 results not only in an increased clearance rate but is also associated with an impaired pH-dependent interaction with VWF propeptide.
Received for publication, September 22, 2003 , and in revised form, November 12, 2003.
* This study was supported by INSERM-NWO Exchange Grant 910-48-603 (to C. V. D. and P. J. L.) and an INSERM AVENIR program grant (to C. V. D.) 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.
To whom correspondence should be addressed: Laboratory for Thrombosis and Haemostasis, Dept. of Haematology (G.03.647), University Medical Center Utrecht, Heidelberglaan 100, 3485 CX Utrecht, The Netherlands. Tel.: 31-30-2507610; Fax: 31-30-2511893; E-mail: p.j.lenting{at}lab.azu.nl.
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