The human platelet antigen-1b (Pro33) variant of αIIbß3 allosterically shifts the dynamic conformational equilibrium of this integrin toward the active state.
J Biol Chem
; 293(13): 4830-4844, 2018 03 30.
Article
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| MEDLINE
| ID: mdl-29462793
ABSTRACT
Integrins are heterodimeric cell-adhesion receptors comprising α and ß subunits that transmit signals allosterically in both directions across the membrane by binding to intra- and extracellular components. The human platelet antigen-1 (HPA-1) polymorphism in αIIbß3 arises from a Leu â Pro exchange at residue 33 in the genu of the ß3 subunit, resulting in Leu33 (HPA-1a) or Pro33 (HPA-1b) isoforms. Although clinical investigations have provided conflicting results, some studies have suggested that Pro33 platelets exhibit increased thrombogenicity. Under flow-dynamic conditions, the Pro33 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 â Pro exchange allosterically shifts the dynamic conformational equilibrium of αIIbß3 toward an active state. Multiple microsecond-long, all-atom molecular dynamics simulations of the ectodomain of the Leu33 and Pro33 isoforms provided evidence that the Leu â 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 αIIbß3 in transfected HEK293 cells, we found that the Pro33 variant in its resting state displays a lower energy transfer than the Leu33 isoform. This finding indicated a larger spatial separation of the cytoplasmic tails in the Pro33 variant. Together, our results indicate that the Leu â Pro exchange allosterically shifts the dynamic conformational equilibrium of αIIbß3 to a structural state closer to the active one, promoting the fully active state and fostering the prothrombotic phenotype of Pro33 platelets.
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Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Trombosis
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Plaquetas
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Transducción de Señal
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Agregación Plaquetaria
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Antígenos de Plaqueta Humana
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Complejo GPIIb-IIIa de Glicoproteína Plaquetaria
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2018
Tipo del documento:
Article
País de afiliación:
Alemania