von Willebrand disease type B: a missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein Ib.

Rabinowitz, Ian; Tuley, Elodee A.; Mancuso, D J; Randi, Anna M.; Firkin, Barry G.; Howard, Margaret A.; Sadler, J. Evan

doi:10.1073/pnas.89.20.9846

Cited by 95 publications

(77 citation statements)

References 40 publications

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“…5). These results are consistent with their respective GOF and loss of function phenotypes found in other assays, explaining the spontaneous binding of VWF to platelet for type 2B VWD (50,51) and ptVWD (42)(43)(44), as well as the ineffective binding of VWF to platelet for type 2M VWD (22,52) …”

Section: Discussionsupporting

confidence: 90%

The N-terminal Flanking Region of the A1 Domain Regulates the Force-dependent Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

Ju¹,

Dong

Crúz

et al. 2013

Journal of Biological Chemistry

196

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Section: Discussionsupporting

confidence: 90%

The N-terminal Flanking Region of the A1 Domain Regulates the Force-dependent Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

Ju¹,

Dong

Crúz

et al. 2013

Journal of Biological Chemistry

196

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“…These map near to the upper face of the domain (Fig. 3) (27). Gly 561 is part of the tight ␤B-␤C turn at the upper front/edge of the domain.…”

Section: Discussionmentioning

confidence: 96%

Crystal Structure of the von Willebrand Factor A1 Domain and Implications for the Binding of Platelet Glycoprotein Ib

Emsley¹,

Crúz²,

Handin³

et al. 1998

Journal of Biological Chemistry

257

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von Willebrand Factor (vWF) is a multimeric protein that mediates platelet adhesion to exposed subendothelium at sites of vascular injury under conditions of high flow/shear. The A1 domain of vWF (vWF-A1) forms the principal binding site for platelet glycoprotein Ib (GpIb), an interaction that is tightly regulated. We report here the crystal structure of the vWF-A1 domain at 2.3-Å resolution. As expected, the overall fold is similar to that of the vWF-A3 and integrin I domains. However, the structure also contains N-and C-terminal arms that wrap across the lower surface of the domain. Unlike the integrin I domains, vWF-A1 does not contain a metal ion-dependent adhesion site motif. Analysis of the available mutagenesis data suggests that the activator botrocetin binds to the right-hand face of the domain containing helices ␣5 and ␣6. Possible binding sites for GpIb are the front and upper surfaces of the domain. Natural mutations that lead to constitutive GpIb binding (von Willebrand type IIb disease) cluster in a different site, at the interface between the lower surface and the terminal arms, suggesting that they disrupt a regulatory region rather than forming part of the primary GpIb binding site. A possible pathway for propagating structural changes from the regulatory region to the ligand-binding surface is discussed. von Willebrand Factor (vWF) 1 is a multimeric protein that mediates platelet adhesion to exposed subendothelium at sites of vascular injury (1). The adhesive properties of vWF are tightly regulated so that plasma vWF does not normally interact with circulating platelets. vWF, however, will bind to platelets after it is "activated" by poorly understood conformational changes that occur after it binds to the vessel wall. A reduction in the plasma concentration of vWF or mutations that impair binding, activation, or assembly of vWF multimers cause von Willebrand disease (vWD), a common bleeding disorder characterized by decreased platelet adhesion and mucocutaneous bleeding (2).vWF-mediated adhesion of platelets to the vessel wall, under the high flow/shear conditions present in circulating blood, is mediated by sequences within the first (A1 domain) and third (A3 domain) A type repeats of vWF. The A1 domain (residues 479 -717) binds to platelet glycoprotein Ib⅐IX⅐V complex (GpIb), subendothelial heparans, cell surface sulfatides (reviewed in Ref. 3), and the non-fibrillar collagen type VI (4). The vWF-A3 domain contains the principal site for binding the fibrillar collagens types I and III (5, 6).Although initially noted in the primary sequence of vWF, the A domain has been subsequently discovered in a large number of cell matrix-associated or adhesive proteins and receptors (7). For example, varying numbers of A domains are found in several of the atypical, short chain collagens. A single A domain is inserted into the sequence of several integrin receptors, where it is generally referred to as the I domain. A/I domains are frequently involved in either cell adhesion or cell ligand interactions...

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“…Studies of this unique abnormality established that plasma VWF was undetectable via ristocetin-induced platelet agglutination, whereas platelet agglutination induced by the botrocetin snake venom confirmed the presence of VWF in plasma (3,4). Two decades following the initial presentation, the G1324S mutation, now classified as a type 2M loss-of-function VWD phenotype, was sequenced, and complementary studies on recombinant VWF harboring this mutation within the A1 domain reproduced the patient's VWF functional characteristics (5). Its sister mutation, G1324A, was later identified having similar loss-of-function characteristics (6,7).…”

Section: The Von Willebrand Factor (Vwf)mentioning

confidence: 96%

Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor

Tischer

Campbell²,

Machha

et al. 2016

Journal of Biological Chemistry

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Unusually large von Willebrand factor (VWF), the first responder to vascular injury in primary hemostasis, is designed to capture platelets under the high shear stress of rheological blood flow. In type 2M von Willebrand disease, two rare mutations (G1324A and G1324S) within the platelet GPIb␣ binding interface of the VWF A1 domain impair the hemostatic function of VWF. We investigate structural and conformational effects of these mutations on the A1 domain's efficacy to bind collagen and adhere platelets under shear flow. These mutations enhance the thermodynamic stability, reduce the rate of unfolding, and enhance the A1 domain's resistance to limited proteolysis. Collagen binding affinity is not significantly affected indicating that the primary stabilizing effect of these mutations is to diminish the platelet binding efficiency under shear flow. The enhanced stability stems from the steric consequences of adding a side chain (G1324A) and additionally a hydrogen bond (G1324S) to His 1322 across the ␤2-␤3 hairpin in the GPIb␣ binding interface, which restrains the conformational degrees of freedom and the overall flexibility of the native state. These studies reveal a novel rheological strategy in which the incorporation of a single glycine within the GPIb␣ binding interface of normal VWF enhances the probability of local unfolding that enables the A1 domain to conformationally adapt to shear flow while maintaining its overall native structure.

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von Willebrand disease type B: a missense mutation selectively abolishes ristocetin-induced von Willebrand factor binding to platelet glycoprotein Ib.

Cited by 95 publications

References 40 publications

The N-terminal Flanking Region of the A1 Domain Regulates the Force-dependent Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

The N-terminal Flanking Region of the A1 Domain Regulates the Force-dependent Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

Crystal Structure of the von Willebrand Factor A1 Domain and Implications for the Binding of Platelet Glycoprotein Ib

Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor

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