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@ARTICLE{Pagani:844002,
      author       = {Pagani, Guilia and Pereira, Joana P. V. and Stoldt, Volker
                      R. and Beck, Andreas and Scharf, Rüdiger E. and Gohlke,
                      Holger},
      title        = {{T}he human platelet antigen-1b variant of
                      $\alpha$$_{{II}b}$β$_{3}$ allosterically shifts the dynamic
                      conformational equilibrium of this integrin toward the
                      active state},
      journal      = {The journal of biological chemistry},
      volume       = {293},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {FZJ-2018-01518},
      pages        = {4830-4844},
      year         = {2018},
      abstract     = {Integrins are heterodimeric cell-adhesion receptors
                      comprising α and β subunits. The human platelet antigen-1
                      (HPA-1) polymorphism in αIIbβ3 arises from a Leu→Pro
                      exchange at residue 33 in the genu of the β3 subunit,
                      resulting in Leu-33 (HPA-1a) or Pro-33 (HPA-1b) isoforms.
                      Although clinical investigations have provided conflicting
                      results, some studies have suggested that Pro-33 platelets
                      exhibit increased thrombogenicity. Under flow-dynamic
                      conditions, the Pro-33 variant displays prothrombotic
                      properties, characterized by increased platelet adhesion,
                      aggregate/thrombus formation, and outside-in signaling.
                      However, the molecular events underlying this prothrombotic
                      phenotype have remained elusive. As residue 33 is located >
                      80 Å away from extracellular binding sites or transmembrane
                      domains, we hypothesized that the Leu→Pro exchange
                      allosterically shifts the dynamic conformational equilibrium
                      of αIIbβ3 toward an active state. Multiple
                      microsecond-long, all-atom molecular dynamics simulations of
                      the ectodomain of the Leu-33 and Pro-33 isoforms provided
                      evidence that the Leu→Pro exchange weakens interdomain
                      interactions at the genu and alters the structural dynamics
                      of the integrin to a more unbent and splayed state. Using
                      FRET analysis of fluorescent proteins fused with αIIbβ3 in
                      transfected HEK293 cells, we found that the Pro-33 variant
                      in its resting state displays a lower energy transfer than
                      the Leu-33 isoform. This finding indicated a larger spatial
                      separation of the cytoplasmic tails in the Pro-33 variant.
                      Together, our results indicate that the Leu→Pro exchange
                      allosterically shifts the dynamic conformational equilibrium
                      of αIIbβ3 to a structural state closer to the active one,
                      promoting the fully active state and fostering the
                      prothrombotic phenotype of Pro-33 platelets.},
      cin          = {JSC / ICS-6},
      ddc          = {570},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)ICS-6-20110106},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511)},
      pid          = {G:(DE-HGF)POF3-511},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29462793},
      UT           = {WOS:000428848300023},
      doi          = {10.1074/jbc.RA118.002149},
      url          = {https://juser.fz-juelich.de/record/844002},
}