Structure-function of platelet glycoprotein Ib-IX

Abstract

The glycoprotein (GP)Ib-IX receptor complex plays a critical role in platelet physiology and pathology. Its interaction with von Willebrand factor (VWF) on the subendothelial matrix instigates platelet arrest at the site of vascular injury and is vital to primary hemostasis. Its reception to other ligands and counter-receptors in the bloodstream also contribute to various processes of platelet biology that are still being discovered. While its basic composition and its link to congenital bleeding disorders were well documented and firmly established more than 25 years ago, recent years have witnessed critical advances in the organization, dynamics, activation, regulation, and functions of the GPIb-IX complex. This review summarizes important findings and identifies questions that remain about this unique platelet mechanoreceptor complex.

Keywords: glycoprotein Ib; mechanoreceptor; platelet; thrombocytopenia; thrombosis.

Figure 1.. Organization and structure of GPIb-IX.

Cartoon illustration of the GPIb-IX complex including GPIbα (black), GPIbβ (green), GPIX (red). The N-terminal LBD of GPIbα is labeled, the membrane-proximal MSD is highlighted in purple, and the trigger sequence therein is highlighted in blue. The complex is held together by strong associations among the transmembrane domains as well as weak associations between GPIbβ and GPIX extracellular domains and potentially the MSD of GPIbα. Binding partners of the GPIbα LBD are listed to the right, including thrombin and VWF-A1. Intracellularly, 14-3-3ζ interacts with the intracellular tails of GPIbβ and GPIbα. FlnA binds to the tail of GPIbα. Binding partners for which a specific binding site has not been identified are listed in gray.

Figure 2.. Multiple sequence alignment of the GPIbα MSD.

(A) MSD sequence of GPIbα orthologs from various species. The MSD, transmembrane domain (TMD), and trigger sequence are demarcated. Residues with identity match to the human sequence are listed in red. The triangle denotes the ADAM17 shedding cleavage site in human GPIbα. (B) Phylogenetic tree constructed from multiple sequence alignment of trigger sequences for each of the species in (a).

Figure 3.. Activation and regulation of GPIb-IX signaling.

(A) The Trigger model of GPIb-IX activation. Binding of VWF or anti-LBD antibodies to the LBD of GPIbα under physiological shear induces MSD unfolding. Neuraminidase (Neu) treatment in the absence of shear also induces MSD unfolding. Unfolding of the MSD leads to exposure of the trigger sequence therein, likely inducing a conformational change in the adjoining GPIbβ/GPIX and subsequent GPIb-IX signaling into the cell. This activation is modulated by anti-GPIbβ MAbs 3G6 (which potentiates activation) and RAM.1 (which inhibits activation). MPαC competitively inhibits 14-3-3ζ binding to the intracellular tail of GPIbα, diminishes its downstream signaling, and reduces cell adhesion to VWF. The membrane-proximal MSD is highlighted in purple, and the trigger sequence therein is highlighted in blue (B) Ectodomain shedding of GPIb-IX induced by ADAM17 cleavage of a site within the MSD induces shear-independent activation. Shedding can be inhibited by the anti-MSD MAb 5G6 or metalloproteinase inhibitors such as GM6001. Note that unfolding of the MSD facilitates ADAM17-mediated shedding of GPIbα.