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mode of action of cAMP and other second messengers is discussed in later sections.

Many Conserved Intracellular Proteins Function in Signal Transduction

In addition to cell-surface receptors and second messengers, two groups of evolutionary conserved proteins function in signal-transduction pathways stimulated by extracellular signals. Here we briefly consider these intracellular signaling proteins; their role in specific pathways is described elsewhere.

GTPase Switch Proteins We introduced the large group of intracellular switch proteins that form the GTPase super-family in Chapter 3. These guanine nucleotide-binding proteins are turned "on" when bound to GTP and turned "off" when bound to GDP (see Figure 3-29). Signal-induced conversion of the inactive to active state is mediated by a guanine nucleotide-exchange factor (GEF), which causes release of GDP from the switch protein. Subsequent binding

► FIGURE 13-8 Switching mechanism for monomeric and trimeric G proteins. The ability of a G protein to interact with other proteins and thus transduce a signal differs in the GTP-bound "on" state and GDP-bound "off" state. (a) In the active "on" state, two domains, termed switch I (green) and switch II (blue), are bound to the terminal y phosphate of GTP through interactions with the backbone amide groups of a conserved threonine and glycine residue. (b) Release of the of GTP, favored by its high intracellular concentration, induces a conformational change in two segments of the protein, termed switch I and switch II, allowing the protein to bind to and activate other downstream signaling proteins (Figure 13-8). The intrinsic GTPase activity of the switch proteins then hydrolyzes the bound GTP to GDP and Pi, thus changing the conformation of switch I and switch II from the active form back to the inactive form. The rate of GTP hydrolysis frequently is enhanced by a GTPase-accelerating protein (GAP), whose activity also may be controlled by extracellular signals. The rate of GTP hydrolysis regulates the length of time the switch protein remains in the active conformation and able to signal downstream.

There are two classes of GTPase switch proteins: trimeric (large) G proteins, which as noted already directly bind to and are activated by certain receptors, and monomeric (small) G proteins such as Ras and various Ras-like proteins. Ras is linked indirectly to receptors via adapter proteins and GEF proteins discussed in the next chapter. All G proteins contain regions like switch I and switch II that modulate the y phosphate by GTPase-catalyzed hydrolysis causes switch I and switch II to relax into a different conformation, the inactive "off" state. Shown here as ribbon models are both conformations of Ras, a monomeric G protein. A similar spring-loaded mechanism switches the a subunit in trimeric G proteins between the active and inactive conformations. [Adapted from I. Vetter and A. Wittinghofer, 2001, Science 294:1299.]

Switch II

(a) GTP-bound "on" state Gly-60 Thr-35

Switch I

(a) GTP-bound "on" state Gly-60 Thr-35

Switch II

Gly-60

Switch II

Thr-35

Gly-60

Thr-35

Switch II

Switch I

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