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@ARTICLE{Huck:476472,
      author       = {Huck, Volker and Chen, Po-Chia and Xu, Emma-Ruoqi and
                      Tischer, Alexander and Klemm, Ulrike and Aponte-Santamaría,
                      Camilo and Mess, Christian and Obser, Tobias and Kutzki,
                      Fabian and König, Gesa and Denis, Cécile V. and Gräter,
                      Frauke and Wilmanns, Matthias and Auton, Matthew and
                      Schneider, Stefan W. and Schneppenheim, Reinhard and Hennig,
                      Janosch and Brehm, Maria A.},
      title        = {{G}ain-of-{F}unction {V}ariant p.{P}ro2555{A}rg of von
                      {W}illebrand {F}actor {I}ncreases {A}ggregate {S}ize through
                      {A}ltering {S}tem {D}ynamics},
      journal      = {Thrombosis and haemostasis},
      volume       = {122},
      number       = {02},
      issn         = {0340-6245},
      address      = {Stuttgart},
      publisher    = {Thieme},
      reportid     = {PUBDB-2022-01749},
      pages        = {226 - 239},
      year         = {2022},
      abstract     = {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.},
      cin          = {EMBL-User / EMBL},
      ddc          = {610},
      cid          = {I:(DE-H253)EMBL-User-20120814 / I:(DE-H253)EMBL-20120731},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P12-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33385180},
      UT           = {WOS:000640018900001},
      doi          = {10.1055/a-1344-4405},
      url          = {https://bib-pubdb1.desy.de/record/476472},
}