Structure and function of the platelet integrin alphaIIbbeta3

Abstract

The platelet integrin alpha(IIb)beta(3) is required for platelet aggregation. Like other integrins, alpha(IIb)beta(3) resides on cell surfaces in an equilibrium between inactive and active conformations. Recent experiments suggest that the shift between these conformations involves a global reorganization of the alpha(IIb)beta(3) molecule and disruption of constraints imposed by the heteromeric association of the alpha(IIb) and beta(3) transmembrane and cytoplasmic domains. The biochemical, biophysical, and ultrastructural results that support this conclusion are discussed in this Review.

Figure 1

Ribbon diagram of the structure of the extracellular portion of α_vβ₃. (A) Bent conformation of α_vβ₃ as it was present in the crystal. (B) Extension of the structure to reveal its domains. Adapted with permission from Annual Review of Cell and Developmental Biology (97).

Figure 2

Cryo-EM reconstruction and rotary-shadowed EM images of α_IIbβ₃. (A) Cryo-EM reconstruction. The resolution is 20 Å. Adapted with permission from Proceedings of the National Academy of Sciences of the United States of America (38). (B and C) Rotary-shadowed EM images. The images in B were obtained in the presence of 1 mM Ca²⁺ and the images in C in the presence of 1 mM Mn²⁺. Reproduced with permission from Blood (19).

Figure 3

Interaction of the α_IIb and β₃ cytoplasmic domains. (A) Backbone ribbon diagram of the α_IIbβ₃ membrane-proximal cytoplasmic domain clasp showing hydrophobic and electrostatic interactions. Reproduced with permission from Cell (52). (B) Model of the changes that may occur in the clasp following talin binding to the β₃ cytoplasmic domain. Adapted with permission from Proceedings of the National Academy of Sciences of the United States of America (53).

Figure 4

Model of the structure of the β₃ TM and cytoplasmic domains. Helices are shown as cylinders. Three different orientations of the β₃ TM domain in the plasma membrane are shown. The membrane-proximal region of the cytoplasmic domain is shaded. Arrows indicate possible interactions between helices. Adapted with permission from Biochemistry (68).

Figure 5

Diagram illustrating the “push-pull” hypothesis for regulation of the α_IIbβ₃ activation state. The white and blue cylinders represent the α_IIb TM and membrane-proximal cytoplasmic domain helices, respectively. The red and green cylinders represent the β₃ TM and membrane-proximal cytoplasmic domain helices, respectively.