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

Abstract

Background: 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).

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

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

Results: 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.

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

Keywords: Bernard-Soulier syndrome; glycoprotein Ib alpha; glycoprotein Ib-IX complex; mechanosensory; unfolded protein response.