Flow-induced elongation of von Willebrand factor precedes tension-dependent activation

Guardado en:

Detalles Bibliográficos
Publicado en:	Nature Communications vol. 8 (Aug 2017), p. 1
Autor principal:	Fu, Hongxia
Otros Autores:	Jiang, Yan, Yang, Darren, Scheiflinger, Friedrich, Wong, Wesley P, Springer, Timothy A
Publicado:	Nature Publishing Group
Materias:	Tension Von Willebrand factor Clotting Elongation Health risk assessment Microfluidics Thromboembolism Environmental
Acceso en línea:	Citation/Abstract Full Text - PDF
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

Descripción
Resumen:	Von Willebrand factor, an ultralarge concatemeric blood protein, must bind to platelet GPIbα during bleeding to mediate hemostasis, but not in the normal circulation to avoid thrombosis. Von Willebrand factor is proposed to be mechanically activated by flow, but the mechanism remains unclear. Using microfluidics with single-molecule imaging, we simultaneously monitored reversible Von Willebrand factor extension and binding to GPIbα under flow. We show that Von Willebrand factor is activated through a two-step conformational transition: first, elongation from compact to linear form, and subsequently, a tension-dependent local transition to a state with high affinity for GPIbα. High-affinity sites develop only in upstream regions of VWF where tension exceeds ~21 pN and depend upon electrostatic interactions. Re-compaction of Von Willebrand factor is accelerated by intramolecular interactions and increases GPIbα dissociation rate. This mechanism enables VWF to be locally activated by hydrodynamic force in hemorrhage and rapidly deactivated downstream, providing a paradigm for hierarchical mechano-regulation of receptor–ligand binding.
ISSN:	2041-1723
DOI:	10.1038/s41467-017-00230-2
Fuente:	Health & Medical Collection