{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T04:09:09Z","timestamp":1781323749746,"version":"3.54.1"},"reference-count":48,"publisher":"Georg Thieme Verlag KG","issue":"02","license":[{"start":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T00:00:00Z","timestamp":1609372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["FOR1543,INST 35\/1134-1 FUGG"],"award-info":[{"award-number":["FOR1543,INST 35\/1134-1 FUGG"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Thromb Haemost"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The multimeric plasma glycoprotein (GP) 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 GPIIb\/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, nuclear magnetic resonance spectroscopy, molecular dynamics simulations on the single C4 domain, and dimeric wild-type 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 does not affect 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 shows 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 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 antithrombotic drug target.<\/jats:p>","DOI":"10.1055\/a-1344-4405","type":"journal-article","created":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T01:10:12Z","timestamp":1609463412000},"page":"226-239","source":"Crossref","is-referenced-by-count":4,"title":["Gain-of-Function Variant p.Pro2555Arg of von Willebrand Factor Increases Aggregate Size through Altering Stem Dynamics"],"prefix":"10.1055","volume":"122","author":[{"given":"Volker","family":"Huck","sequence":"first","affiliation":[{"name":"Department of Dermatology and Venereology, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"},{"name":"Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Chia","family":"Chen","sequence":"first","affiliation":[{"name":"Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma-Ruoqi","family":"Xu","sequence":"first","affiliation":[{"name":"European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Tischer","sequence":"additional","affiliation":[{"name":"Division of Hematology, Mayo Clinic, Rochester, Minnesota, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Klemm","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilo","family":"Aponte-Santamar\u00eda","sequence":"additional","affiliation":[{"name":"Max Planck Tandem Group in Computational Biophysics, University of los Andes, Bogot\u00e1, Colombia"},{"name":"Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Mess","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Obser","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Kutzki","sequence":"additional","affiliation":[{"name":"Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany"},{"name":"Institute of Physical Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gesa","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile V.","family":"Denis","sequence":"additional","affiliation":[{"name":"Laboratory of Hemostasis, Inflammation and Thrombosis, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale UMR_1176, Universit\u00e9 Paris-Saclay, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frauke","family":"Gr\u00e4ter","sequence":"additional","affiliation":[{"name":"Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany"},{"name":"Molecular Biomechanics Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Wilmanns","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany"},{"name":"University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Auton","sequence":"additional","affiliation":[{"name":"Division of Hematology, Mayo Clinic, Rochester, Minnesota, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan W.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Schneppenheim","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, University 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