Identification of a juxtamembrane mechanosensitive domain in the platelet mechanosensor glycoprotein Ib-IX complex

Abstract

Key Points Pulling of VWF A1 domain that is engaged to GPIb-IX induces unfolding of a hitherto unidentified mechanosensitive domain in GPIbα. The spatial proximity of the mechanosensitive domain to GPIbβ and GPIX suggests a novel mechanism of platelet mechanosensing.

Acquired von Willebrand syndrome associated with left ventricular assist device

“…83 The formation of VWFcrosslinked platelets through supraphysiologic shear in an LVAD would, therefore, increase force application, leading to VWF-mediated mechanotransduction/platelet activation and VWF proteolysis. 71,92,93 In the second scenario, shear-driven VWF immobilization on such substrates as collagen and the biomaterial surfaces of LVADs could result in changes to VWF conformation. This was originally demonstrated using atomic force microscopy on hydrophobic substrates in which the application of wall shear stress .3.5 Pa triggered VWF unfolding.…”

Megakaryocytic Maturation in Response to Shear Flow Is Mediated by the Activator Protein 1 (AP-1) Transcription Factor via Mitogen-activated Protein Kinase (MAPK) Mechanotransduction

“…Mechanotransduction, the process in which cells convert biomechanical stimuli into molecular signaling, has been extensively studied in endothelial cells (11)(12)(13)(14)(15), but also in other cell types such as platelets (16,17), lymphocytes (18), bone cells (19,20), vascular smooth muscle cells (21)(22)(23), chondrocytes (21), and tumor cells (24,25). In endothelial cells, the MAPK pathways p38, ERK, and JNK are implicated in transducing shear-flow stimuli (26 -28).…”

Platelets and physics: How platelets “feel” and respond to their mechanical microenvironment

“…It was recently discovered that the stalk region acts as a mechanosensor that unfolds under pulling forces [29]. This unfolding occurs at forces ranging from 5 to 20 pN, which is a range similar to that reported for catch and flex bonds [29]. It is likely that the interplay between the unfolding of the stalk region and the binding kinetics of vWF-A1 under hydrodynamic forces governs platelet recruitment to the vessel wall.…”

“…It is likely that the interplay between the unfolding of the stalk region and the binding kinetics of vWF-A1 under hydrodynamic forces governs platelet recruitment to the vessel wall. It is also proposed that unfolding of this stalk region induces conformational changes in GPIbβ and GPIX, which triggers further signaling [29].…”

“…Following the leucine-rich repeat domain of the Nterminus, GPIbα contains a highly glycosylated macroglycopeptide region; a stalk region; a pair of cysteine residues that connect to GPIbβ via disulfide bonds; a transmembrane helix; and a relatively short cytoplasmic domain at the C-terminus [27,28]. It was recently discovered that the stalk region acts as a mechanosensor that unfolds under pulling forces [29]. This unfolding occurs at forces ranging from 5 to 20 pN, which is a range similar to that reported for catch and flex bonds [29].…”