Shear-Induced Unfolding Activates von Willebrand Factor A2 Domain for Proteolysis

Details Shear-Induced Unfolding Activates von Willebrand Factor A2 Domain for Proteolysis Shear-Induced Unfolding Activates von Willebrand Factor A2 Domain for Proteolysis

2009-04-24

arxiv.org/abs/0904.3951v1

J. Thromb. Haemost. 2009 (7), 2096-2105.

Physics

Biological Physics

Scientific paper

10.1111/j.1538-7836.2009.03640.x

To avoid pathological platelet aggregation by von Willebrand factor (VWF), VWF multimers are regulated in size and reactivity for adhesion by ADAMTS13-mediated proteolysis in a shear flow dependent manner. We examined if tensile stress in VWF under shear flow activates the VWF A2 domain for cleavage by ADAMTS13 using molecular dynamics simulations. We indeed observed stepwise unfolding of A2 and exposure of its deeply buried ADAMTS13 cleavage site. Interestingly, disulfide bonds in the adjacent and highly homologous VWF A1 and A3 domains obstruct their mechanical unfolding. We generated a full length mutant VWF featuring a homologous disulfide bond in A2 (N1493C and C1670S), in an attempt to lock A2 against unfolding. We find this mutant to feature ADAMTS13-resistant behavior in vitro. Our results yield molecular-detail evidence for the force-sensoring function of VWF A2, by revealing how tension in VWF due to shear flow selectively exposes the A2 proteolysis site to ADAMTS13 for cleavage while keeping the folded remainder of A2 intact and functional. We find the unconventional knotted Rossman fold of A2 to be the key to this mechanical response, tailored for regulating VWF size and activity. Based on our model we can explain the pathomechanism of some natural mutations in the VWF A2 domain that significantly increase the cleavage by ADAMTS13 without shearing or chemical denaturation, and provide with the cleavage-activated A2 conformation a structural basis for the design of inhibitors for VWF type 2 diseases.

Affiliated with

Also associated with

No associations

Rating

Shear-Induced Unfolding Activates von Willebrand Factor A2 Domain for Proteolysis does not yet have a rating. At this time, there are no reviews or comments for this scientific paper.

If you have personal experience with Shear-Induced Unfolding Activates von Willebrand Factor A2 Domain for Proteolysis, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Shear-Induced Unfolding Activates von Willebrand Factor A2 Domain for Proteolysis will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFWR-SCP-O-671249