Receptors are activated by dimerization

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28 SIGNAL TRANSDUCTION (Full Edition)

9 Receptors are activated by dimerization

The ability of a species of kinase to phosphorylate itself is referred to as autophosphorylation. Autophosphorylation does not necessarily occur on the same polypeptide chain as the catalytic site; for example, in a dimer, each subunit may phosphorylate the other.

Ligand binding to receptor monomers causes them to dimerize by interactions between the extracellular domains.
Dimerization is made possible by the ability of membrane proteins to move laterally within the membrane bilayer.
Dimerization activates the cytoplasmic domains by an autophosphorylation in which the kinase activity of each monomer phosphorylates the other monomer.

A key question in the concept of how a signal is transduced across a membrane is how binding of the ligand to the extracellular domain activates the catalytic domain in the cytoplasm. The general principle is that a conformational change is induced that affects the overall organization of the receptor. An important factor in this interaction is that membrane proteins have a restricted ability to diffuse laterally (in contrast with the continuous motion of the lipids in the bilayer). This enables their state of aggregation to be controlled by external events.

Figure 28.16

The principle underlying signal transduction by a tyrosine kinase receptor is that ligand binding to the extracellular domain triggers dimerization; this causes a conformational change in the cytoplasmic domain that activates the tyrosine kinase catalytic activity.

Lateral movement plays a key role in transmitting information from one side of the membrane to the other. Figure 28.16 shows that binding of ligand induces a conformation change in the N-terminal region of a group I receptor that causes the extracellular domains to dimerize. This causes the transmembrane domains to diffuse laterally, bringing the cytoplasmic domains into juxtaposition. The stabilization of contacts between the C-terminal cytosolic domains causes a change in conformation that activates the kinase activity. In some cases, phosphorylation also causes the receptor to interact with proteins present on the cytoplasmic surface of a coated pit, leading to endocytosis of the receptor. An extreme case of lateral diffusion is seen in certain cases of receptor internalization, when receptors of a given type aggregate into a "cap" in response to an extracellular stimulus.

Figure 28.17

Binding of ligand to the extracellular domain can induce aggregation in several ways. The common feature is that this causes new contacts to form between the cytoplasmic domains.

Figure 28.17 shows that dimerization can take several forms (for review see 2898). The most common is that a ligand binds to one or to both monomers to induce them to dimerize (2905). A variation is that a dimeric ligand binds to two monomers to bring them together (2902). In the case of the insulin receptor family, the ligand binds to a dimeric receptor (which is stabilized by extracellular disulfide bridges) to cause an intramolecular change of conformation. The major consequence of dimerization is to allow transmission of a conformational change from the extracellular domain to the cytoplasmic domain without requiring a change in the structure of the transmembrane region (793; for review see 307; 2266).

Dimerization initiates the signaling pathway by triggering an autophosphorylation in the cytoplasmic domains of the receptor. When the two cytoplasmic domains are brought together in the dimer, each phosphorylates the other. It is necessary for both subunits to have kinase activity for the receptor to be activated; if one subunit is defective in kinase activity, the dimer cannot be activated.

Autophosphorylation has two consequences. Phosphorylation of tyrosines in the kinase domain causes the "activation loop" to swing away from the catalytic center, thus activating the ability of the kinase to bind its substrate Figure 28.14. Phosphorylation of tyrosines at other regions of the cytoplasmic domain provides the means by which substrate proteins are enabled to bind to the receptor. The existence of these phosphorylated tyrosine(s) in specific signaling motifs causes the cytoplasmic domain to associate with its target proteins (see Receptor kinases activate signal transduction pathways) (for review see 298; 305).

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