Structural biology of glycoprotein IIb-IIIa

Abstract

Glycoprotein IIb-IIIa (GPIIb-IIIa), a calcium-dependent heterodimer whose expression is restricted to platelets and megakaryocytes, contains a binding site for protein ligands such as fibrinogen and von Willebrand factor (vWf) whose exposure by platelet stimulation is a prerequisite for platelet aggregation. GPIIb-IIIa heterodimers are assembled from nascent GPIIb and GPIIIa subunits in the calcium-rich environment of the endoplasmic reticulum, and correctly folded heterodimers are transported from the endoplasmic reticulum through the Golgi apparatus to the cell surface. Agonist stimulation of platelets produces a conformational change in GPIIb-IIIa that exposes its ligand binding site, a process termed "insideout" signaling. This signaling process, by interacting with the cytoplasmic extensions of GPIIb and GPIIIa, converts the heterodimer from an inactive to an activated state capable of binding soluble ligands.