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Gain-of-function variant p.Pro2555Arg of von Willebrand factor increases aggregate size through altering stem dynamics.

Abstract：

:The multimeric plasma glycoprotein von Willebrand factor (VWF) is best known for recruiting platelets to sites of injury during primary hemostasis. Generally, mutations in the VWF gene lead to loss of hemostatic activity and thus the bleeding disorder von Willebrand Disease. By employing cone and platelet aggregometry and microfluidic assays, we uncovered a platelet glycoprotein (GP)IIb/IIIa-dependent prothrombotic gain-of-function (GOF) for variant p.Pro2555Arg, located in the C4-domain, leading to an increase in platelet aggregate size. We performed complementary biophysical and structural investigations using circular dichroism spectra, small angle X-ray scattering, NMR spectroscopy, molecular dynamics simulations on the single C4-domain and dimeric wildtype and p.Pro2555Arg constructs. C4-p.Pro2555Arg retained the overall structural conformation with minor populations of alternative conformations exhibiting increased hinge flexibility and slow conformational exchange. The dimeric protein becomes disordered and more flexible. Our data suggest that the GOF is not affecting the binding affinity of the C4-domain for GPIIb/IIIa. Instead, the increased VWF dimer flexibility enhances temporal accessibility of platelet binding sites. Using an interdisciplinary approach, we revealed that p.Pro2555Arg is the first VWF variant, which increases platelet aggregate size and show a shear-dependent function of the VWF stem region, which can become hyperactive through mutations. Prothrombotic GOF variants of VWF are a novel concept of a VWF-associated pathomechanism of thromboembolic events, which is of general interest to vascular health but which is not yet considered in diagnostics. Thus, awareness should be raised for the risk they pose. Furthermore, our data implicate the C4-domain as a novel anti-thrombotic drug target.

journal_name

Thromb Haemost

journal_title

Thrombosis and haemostasis

authors

Huck V,Chen PC,Xu ER,Tischer A,Klemm U,Aponte-Santamaría C,Mess C,Obser T,Kutzki F,König G,Denis C,Gräter F,Wilmanns M,Auton M,Schneider SW,Schneppenheim R,Hennig J,Brehm MA

doi

10.1055/a-1344-4405

subject

Has Abstract

pub_date

2020-12-31 00:00:00

eissn

0340-6245

issn

2567-689X

pub_type

杂志文章

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Gain-of-function variant p.Pro2555Arg of von Willebrand factor increases aggregate size through altering stem dynamics.