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| 024 | 7 | _ | |a 10.1074/jbc.RA118.002149 |2 doi |
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| 082 | _ | _ | |a 570 |
| 100 | 1 | _ | |a Pagani, Guilia |0 P:(DE-HGF)0 |b 0 |
| 245 | _ | _ | |a The human platelet antigen-1b variant of $\alpha$$_{IIb}$β$_{3}$ allosterically shifts the dynamic conformational equilibrium of this integrin toward the active state |
| 260 | _ | _ | |a Bethesda, Md. |c 2018 |b Soc. |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 520 | _ | _ | |a 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. |
| 536 | _ | _ | |a 511 - Computational Science and Mathematical Methods (POF3-511) |0 G:(DE-HGF)POF3-511 |c POF3-511 |f POF III |x 0 |
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| 700 | 1 | _ | |a Pereira, Joana P. V. |0 P:(DE-HGF)0 |b 1 |
| 700 | 1 | _ | |a Stoldt, Volker R. |0 P:(DE-HGF)0 |b 2 |
| 700 | 1 | _ | |a Beck, Andreas |0 P:(DE-HGF)0 |b 3 |
| 700 | 1 | _ | |a Scharf, Rüdiger E. |0 P:(DE-HGF)0 |b 4 |
| 700 | 1 | _ | |a Gohlke, Holger |0 P:(DE-Juel1)172663 |b 5 |e Corresponding author |u fzj |
| 773 | _ | _ | |a 10.1074/jbc.RA118.002149 |g p. jbc.RA118.002149 - |0 PERI:(DE-600)1474604-9 |p 4830-4844 |t The journal of biological chemistry |v 293 |y 2018 |x 0021-9258 |
| 856 | 4 | _ | |y Published on 2018-03-30. Available in OpenAccess from 2019-03-30. |u https://juser.fz-juelich.de/record/844002/files/J.%20Biol.%20Chem.-2018-Pagani-4830-44-1.pdf |
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