Principles of cell signaling - UT Southwestern

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39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 592 Ligand A 14.3 Receptors sense diverse stimuli but initiate a limited repertoire of cellular signals Key concepts • Receptors contain a ligand-binding domain and an effector domain. • Receptor modularity allows a wide variety of signals to use a limited number of regulatory mechanisms. • Cells may express different receptors for the same ligand. • The same ligand may have different effects on the cell depending on the effector domain of its receptor. Receptors mediate responses to amazingly diverse extracellular messenger molecules; hence, the cell must express a large number of receptor varieties, each able to bind its extracellular ligand. In addition, each receptor must be able to initiate a cellular response. Receptors, thus, contain two functional domains: a ligandbinding domain and an effector domain, which may or may not correspond to definable structural domains within the protein. The separation of ligand-binding and effector functions allows receptors for diverse ligands to produce a limited number of evolutionarily conserved intracellular signals through the action of a few effector domains. In fact, there are Receptors have a ligand-binding domain and an effector domain Output 1 Output 2 Ligand A Output 1 Ligand B Output 1 CHIMERIC RECEPTOR Ligand C LBD1 LBD1 LBD1 LBD2 LBD3 ED1 ED2 ED1 ED1 Output 2 ED2 FIGURE 14.2 Receptors can be thought of as composed of two functional domains, a ligand-binding domain (LBD) and an effector domain (ED). The twodomain property implies that two receptors that respond to different ligands (middle) could initiate the same function by activating similar effector domains, or that a cell could express two receptor isoforms (left) that respond to the same ligand with distinct cellular effects mediated by different effector domains. It also implies that one can create an artificial chimeric receptor with novel properties. only a limited number of receptor families, which are related by their conserved structures and signaling functions (see Figure 14.1). There are several useful correlates to the two-domain nature of receptors. For example, a cell can control its responsiveness to an extracellular signal by regulating the synthesis or degradation of a receptor or by regulating the receptor’s activity (see 14.10 Cellular signaling is remarkably adaptive). In addition, the nature of a response is generally determined by the receptor and its effector domain rather than any physicochemical property of the ligand. FIGURE 14.2 illustrates the concept that a ligand may bind to more than one kind of receptor and elicit more than one type of response, or several different ligands may all act identically by binding to functionally similar receptors. For example, the neurotransmitter acetylcholine binds to two classes of receptors. Members of one class are ion channels; members of the other regulate G proteins. Similarly, steroid hormones bind both to nuclear receptors, which bind chromatin and regulate transcription, and to other receptors in the plasma membrane. Conversely, when multiple ligands bind to receptors of the same biochemical class, they generate similar intracellular responses. For example, it is not uncommon for a cell to express several distinct receptors that stimulate production of the intracellular signaling molecule cAMP. The effect of the receptor on the cell will also be determined significantly by the biology of the cell and its state at any given time. Ligand binding and effector domains may evolve independently in response to varied selective pressures. For example, mammalian and invertebrate rhodopsins transduce their signal through different effector G proteins (G t and G q , respectively). Another example is calmodulin, a small calcium-binding regulatory protein in animals, which in plants appears as a distinct domain in larger proteins. The receptor’s two-domain nature allows the cell to regulate the binding of ligand and the effect of ligand independently. Covalent modification or allosteric regulation can alter ligand-binding affinity, the ability of the ligand-bound receptor to generate its signal or both. We will discuss these concepts further in 14.13 Cellular signaling uses both allostery and covalent modification. Receptors can be classified either according to the ligands they bind or the way in which they signal. Signal output, which is character- 592 CHAPTER 14 Principles of cell signaling
39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 593 istic of the effector domain, usually correlates best with overall structure and sequence conservation. (Receptor families grouped by their functions are the organizational basis of the second half of this chapter.) However, classifying receptors pharmacologically, according to their specificity for ligands, is particularly useful for understanding the organization of endocrine and neuronal systems and for categorizing the multiple physiological responses to drugs. Expression of a receptor that is not normally expressed in a cell is often sufficient to confer responsiveness to that receptor’s ligand. This responsiveness often occurs because the cell expresses the other components necessary for propagating the intracellular signal from the receptor. The precise nature of the response will reflect the biology of the cell. Experimentally, responsiveness to a compound can be induced by introducing the cDNA that encodes the receptor. For example, mammalian receptors may be expressed in yeast, such that the yeast respond visibly to receptor ligands, thus providing a way to screen for new chemicals (drugs) that activate the receptor. Finally, it is possible to create chimeric receptors by fusing the ligand-binding domain from one receptor with the effector domain from a different receptor (Figure 14.2). Such chimeras can mediate novel responses to the ligand. With genetic modification of the ligandbinding domain, receptors can be reengineered to respond to novel ligands. Thus, scientists can manipulate cell functions with nonbiological compounds. 14.4 Receptors are catalysts and amplifiers Key concepts • Receptors act by increasing the rates of key regulatory reactions. • Receptors act as molecular amplifiers. Receptors act to accelerate intracellular functions and are, thus, functionally analogous to enzymes or other catalysts. Some receptors, including the protein kinases, protein phosphatases, and guanylate cyclases, are themselves enzymes and thus classical biochemical catalysts. More generally, however, receptors use the relatively small energy of ligand binding to accelerate reactions that are driven by alternative energy sources. For example, receptors that are ion channels catalyze the movement of ions across membranes, a process driven by the electrochemical potential developed by distinct ion pumps. G protein-coupled receptors and other guanine nucleotide exchange factors catalyze the exchange of GDP for GTP on the G protein, an energetically favored process dictated by the cell’s nucleotide energy balance. Transcription factors accelerate the formation of the transcriptional initiation complex, but transcription itself is energetically driven by multiple steps of ATP and dNTP hydrolysis. As catalysts, receptors enhance the rates of reactions. Most signaling involves kinetic rather than thermodynamic regulation; that is, signaling events change reaction rates rather than their equilibria (see the next section). Thus, signaling is similar to metabolic regulation, in which specific reactions are chosen according to their rates, with thermodynamic driving forces playing only a supportive role. In all signaling reactions, receptors use their catalytic activities to function as molecular amplifiers. Directly or indirectly, a receptor generates a chemical signal that is huge, both energetically and with respect to the number of molecules recruited by a single receptor. Molecular amplification is a hallmark of receptors and many other steps in cellular signaling pathways. 14.5 Ligand binding changes receptor conformation Key concepts • Receptors can exist in active or inactive conformations. • Ligand binding drives the receptor toward the active conformation. A central mechanistic question in receptor function is how the binding of a signaling molecule to the ligand-binding domain increases the activity of the effector domain. The key to this question is that receptors can exist in multiple molecular conformations, some active for signaling and others inactive. Ligands shift the conformational equilibrium among these conformations. The structural changes that occur during the receptor’s inactive-active isomerization and how ligand binding drives these changes are exciting areas of biophysical research. However, the basic concept can be described simply in terms of coupling the conformational isomerizations of the ligandbinding and effector domains. 14.5 Ligand binding changes receptor conformation 593
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