Structural biology of glycoprotein IIb-IIIa

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 ave assembled from nascent GPIIb and GPIIIa subunits in the calcium-rich environment of the endoplasmic veticulum, and correctly folded heterodimers ave 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 ''inside-out'' 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.