Shear-dependent morphology of von Willebrand factor bound to immobilized collagen

Novák, Levente; Deckmyn, Hans; Damjanovich, Sándor; Hársfalvi, Jolán

doi:10.1182/blood.v99.6.2070

Cited by 40 publications

(33 citation statements)

References 22 publications

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“…In support of the proposition that shear causes large scale changes in protein conformation, surfaceimmobilized VWF has been shown to extend from a globular to an unfolded state upon application of fluid shear (47). Others suggest, however, that this observation may be substrate specific because VWF immobilized on collagen does not undergo similar changes in response to fluid flow (48). In support of the proposition that subtle changes are sufficient for functional alterations, x-ray studies show how point mutations in the A1-domain and GpIb receptor enhance VWF-GpIb binding affinity, without dramatically altering protein structure (19).…”

Section: Discussionmentioning

confidence: 82%

Solution Structure of Human von Willebrand Factor Studied Using Small Angle Neutron Scattering

Singh

Shankaran

Beauharnois

et al. 2006

Journal of Biological Chemistry

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von Willebrand factor (VWF) binding to platelets under high fluid shear is an important step regulating atherothrombosis. We applied light and small angle neutron scattering to study the solution structure of human VWF multimers and protomer. Results suggest that these proteins resemble prolate ellipsoids with radius of gyration (R g ) of ϳ75 and ϳ30 nm for multimer and protomer, respectively. The ellipsoid dimensions/radii are 175 ؋ 28 nm for multimers and 70 ؋ 9.1 nm for protomers. Substructural repeat domains are evident within multimeric VWF that are indicative of elements of the protomer quarternary structure (16 nm) and individual functional domains (4.5 nm). Amino acids occupy only ϳ2% of the multimer and protomer volume, compared with 98% for serum albumin and 35% for fibrinogen. VWF treatment with guanidine⅐HCl, which increases VWF susceptibility to proteolysis by ADAMTS-13, causes local structural changes at length scales <10 nm without altering protein R g . Treatment of multimer but not protomer VWF with random homobifunctional linker BS 3 prior to reduction of intermonomer disulfide linkages and Western blotting reveals a pattern of dimer and trimer units that indicate the presence of stable intermonomer non-covalent interactions within the multimer. Overall, multimeric VWF appears to be a loosely packed ellipsoidal protein with non-covalent interactions between different monomer units stabilizing its solution structure. Local, and not large scale, changes in multimer conformation are sufficient for ADAMTS-13-mediated proteolysis.von Willebrand factor (VWF) 2 is a large, multidomain glycoprotein that is present in human blood and in secretory granules of endothelial cells and platelets (1-3). This protein occurs both as a protomer and in multimeric form. The ϳ500-kDa protomer consists of two identical monomer subunits linked at the C terminus by disulfide bonds. Linear multimers formed by cysteine-cysteine linkages near the N terminus result in a molecular mass of Ͼ10,000 kDa.VWF serves many functions. The binding of surface-immobilized VWF to platelet receptor GpIb␣ results in intermolecular bonds with high tensile strength (4, 5). This molecular interaction allows platelet capture at sites of vascular injury under high fluid shear conditions. The binding of plasma VWF to platelet receptor GpIb␣ under high hydrodynamic shear also leads to platelet activation and subsequent platelet arrest (6). Various mutations in VWF result in the bleeding defects that characterize von Willebrand disease (1). In blood, VWF binding to pro-coagulation factor VIII increases factor VIII lifetime in circulation. Finally, the size of VWF and its response to fluid flow are key determinants in regulating protein function under physiological and pathological conditions. In support of this, the life threatening systemic illness thrombotic thrombocytopenic purpura (TTP) is attributed to the presence of very large VWF multimers, which are caused by the malfunction or absence of a metalloprotease termed ADAMTS-13 ("a disintegr...

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Section: Discussionmentioning

confidence: 82%

Solution Structure of Human von Willebrand Factor Studied Using Small Angle Neutron Scattering

Singh

Shankaran

Beauharnois

et al. 2006

Journal of Biological Chemistry

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“…Earlier studies demonstrated a shear stress-induced conformational change of VWF from a globular state to an extended chain upon immobilization on an artificial hydrophobic surface [40]. We, in contrast, were not able to show such a large overall shear-induced morphologic shape change on VWF immobilized on collagen but did not exclude small-scale effects of shear on one or more VWF domains [41]. Surface properties itself have an effect on VWF shape [42].…”

Section: Interaction Of Vwf With the Gpib-ix-v Complexmentioning

confidence: 73%

Inhibition of Platelet Glycoprotein Ib and Its Antithrombotic Potential

Vanhoorelbeke¹,

Ulrichts

Walle³

et al. 2007

CPD

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The platelet receptor glycoprotein (GP)Ib-IX-V complex plays a dominant role in the first steps of platelet adhesion and arterial thrombus formation. Through its interaction with the multimeric plasma protein von Willebrand factor (VWF), which is bound to the damaged subendothelial structures, GPIb-IX-V tethers the platelets from the flowing blood thereby slowing them down. This step is a prerequisite for the collagen receptors to participate in firm adhesion resulting in the formation of a first platelet layer which is the basis for further thrombus formation. Recently, other ligands for GPIb-IX-V besides the extensively studied VWF have been identified, such as: alpha-thrombin, coagulation factor XII (FXII), high molecular weight kininogen (HMWK), factor XI (FXI), integrin Mac-1 and P-selectin. In this review, the interaction of GPIb-IX-V with its different ligands is described and the anticipated or demonstrated in vivo effects are discussed.

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“…Therefore we had to employ AFM imaging of dried samples. Dry AFM imaging has previously been used to study binding of SPARC (Wang et al, 2005) and vWF (Novak et al, 2002) to collagen type I and of laminin to collagen type IV (Chen and Hansma, 2000). The basic morphology of DDR1-Fc dimers and collagen was found to be very similar in fluid vs. dry state based on our previous studies and our current results.…”

Section: Discussionmentioning

confidence: 99%

Oligomerization of DDR1 ECD affects receptor–ligand binding

Yeung

Chmielewski

Mihai

et al. 2013

Journal of Structural Biology

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Discoidin Domain Receptor 1 (DDR1) is a widely expressed receptor tyrosine kinase (RTK) which regulates cell differentiation, proliferation and migration and remodeling of the extracellular matrix. Collagen(s) are the only known ligand for DDR1. We have previously reported that collagen stimulation leads to oligomerization of the full length receptor. In this study we investigated the effect of oligomerization of the DDR1 extracellular domain (ECD) pre and post ligand binding. Solid phase binding assays showed that oligomers of recombinant DDR1-Fc bound more strongly to collagen compared to dimeric DDR1-Fc alone. In addition, DDR1-Fc itself could oligomerize upon in-vitro binding to collagen when examined using atomic force microscopy. Inhibition of dynamin mediated receptor endocytosis could prevent ligand induced endocytosis of DDR1-YFP in live cells. However inhibition of receptor endocytosis did not affect DDR1 oligomerization. In summary our results demonstrate that DDR1 ECD plays a crucial role in receptor oligomerization which mediates high-affinity interactions with its ligand.

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Shear-dependent morphology of von Willebrand factor bound to immobilized collagen

Cited by 40 publications

References 22 publications

Solution Structure of Human von Willebrand Factor Studied Using Small Angle Neutron Scattering

Solution Structure of Human von Willebrand Factor Studied Using Small Angle Neutron Scattering

Inhibition of Platelet Glycoprotein Ib and Its Antithrombotic Potential

Oligomerization of DDR1 ECD affects receptor–ligand binding

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