Unaccompanied mechanosensory domain mediates low expression of glycoprotein Ibα: implications for Bernard-Soulier...

Disruption of protein folding or inter-subunit interactions in the platelet glycoprotein (GP)Ib-IX complex leads to its abnormally low expression in the plasma membrane, the hallmark of Bernard-Soulier syndrome (BSS).

To discover the molecular mechanism by which GPIbα in the absence of GPIbβ and GPIX subunits is targeted for rapid degradation.

The expression of GPIbα mutants with deletion or replacement of various domains were measured in transiently transfected Chinese hamster ovary cells.

We report evidence to suggest that induction of the unfolded protein response by the unaccompanied mechanosensory domain (MSD) is a major factor for intracellular degradation and low expression of GPIbα. Removal of the MSD produced the first GPIbα variant that, even in the absence of GPIbβ and GPIX, expressed at a level comparable to that of wild-type GPIbα in the GPIb-IX complex, while retaining its native ligand-binding activity.

Our finding has important implications on the molecular pathogenesis of BSS and the function of the GPIb-IX complex.