A

FIGURE 3-2 Integrin activation. A, The integrins on blood leukocytes are normally in a low-affinity state. If a leukocyte comes close to endothelial cells, such as when selectin-dependent rolling of leukocytes occurs, then chemokines displayed on the endothelial surface can bind chemokine receptors on the leukocyte. Chemokine receptor signaling then occurs, which activates the leukocyte integrins, increasing their affinity for their ligands on the endothelial cells. B, Ribbon diagrams are shown of bent and extended conformations of a leukocyte integrin, corresponding to low- and high-affinity states, respectively. (B From Takagi J, and TA Springer. Integrin activation and structural rearrangement. Immunological Reviews 186:141-163, 2002.)

FIGURE 3-2 Integrin activation. A, The integrins on blood leukocytes are normally in a low-affinity state. If a leukocyte comes close to endothelial cells, such as when selectin-dependent rolling of leukocytes occurs, then chemokines displayed on the endothelial surface can bind chemokine receptors on the leukocyte. Chemokine receptor signaling then occurs, which activates the leukocyte integrins, increasing their affinity for their ligands on the endothelial cells. B, Ribbon diagrams are shown of bent and extended conformations of a leukocyte integrin, corresponding to low- and high-affinity states, respectively. (B From Takagi J, and TA Springer. Integrin activation and structural rearrangement. Immunological Reviews 186:141-163, 2002.)

CHEMOKiNES AND CHEMOKiNE RECEPTORS 41

receptor-induced inside-out signaling involves GTP-binding proteins (described in more detail later), eventually leading to the association of RAP family molecules and cytoskeleton-interacting proteins with the cytoplas-mic tails of the integrin proteins. The resulting affinity changes are a consequence of conformational changes in the extracellular domains. In the low-affinity state, the stalks of the extracellular domains of each integrin subunit appear to be bent over, and the ligand-binding globular heads are close to the membrane. In response to alterations in the cytoplasmic tail, the stalks extend in switchblade fashion, bringing the globular heads away from the membrane to a position where they more effectively interact with their ligands (see Fig. 3-2).

Chemokines also induce membrane clustering of inte-grins. This results in increased avidity of integrin interactions with ligands on the endothelial cells, and therefore tighter binding of the leukocytes to the endothelium.

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