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J Thromb Haemost. 2010 Dec;8(12):2778-88. doi: 10.1111/j.1538-7836.2010.04094.x.

Disulfide bond reduction of von Willebrand factor by ADAMTS-13.

Author information

1
Section of Thrombosis Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.

Abstract

BACKGROUND:

von Willebrand factor (VWF) released from endothelial cells is rich in ultra-large (UL) multimers that are intrinsically active in binding platelets, whereas plasma-type VWF multimers require shear stress to be activated. This functional difference may be attributed to thiols exposed on the surface of plasma-type VWF multimers, but not on ULVWF multimers. Shear stress induces the exposed thiols to form disulfide bonds between laterally apposed plasma-type VWF multimers, leading to enhanced VWF binding to platelets.

OBJECTIVES:

We tested a hypothesis that ADAMTS-13 has a disulfide bond reducing activity that regulates shear-induced thiol-disulfide exchange of VWF.

METHODS:

Thiol blocking agents and active thiol bead capturing were used to identify and locate this activity, along with truncated ADAMTS-13 mutants.

RESULTS:

ADAMTS-13 contains a disulfide bond reducing activity that primarily targets disulfide bonds in plasma-type VWF multimers induced by high shear stress or formed with thiol beads, but not disulfide bonds in native multimeric structures. Cysteine thiols targeted by this activity are in the VWF C-domain and are known to participate in shear-induced thiol-disulfide exchange. ADAMTS-13 contains cysteine thiols that remain exposed after being subjected to hydrodynamic forces. Blocking these active thiols eliminates this reducing activity and moderately decreases ADAMTS-13 activity in cleaving ULVWF strings anchored to endothelial cells under flow conditions, but not under static conditions. This activity is located in this C-terminal region of ADAMTS-13.

CONCLUSIONS:

This novel disulfide-bond-reducing activity of ADAMTS-13 may prevent covalent lateral association and increased platelet adherence of plasma-type VWF multimers induced by high fluid shear stress.

Comment in

PMID:
20946172
PMCID:
PMC2999661
DOI:
10.1111/j.1538-7836.2010.04094.x
[Indexed for MEDLINE]
Free PMC Article

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