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Cell_Biology_Alberts_710	Cell_Biology_Alberts	Humans have invented many different types of mechanical pumps, and it should not be surprising that cells also contain membrane-bound pumps that Figure 3–76 The abC (aTP-binding cassette) transporter, a protein machine that pumps molecules through a membrane. (A) How this large family of transporters pumps molecules into the cell in bacteria. As indicated, the binding of two molecules of ATP causes the two ATP-binding domains to clamp together tightly, opening a channel to the cell exterior. The binding of a substrate molecule to the extracellular face of the protein complex then triggers ATP hydrolysis followed by ADP release, which opens the cytoplasmic gate; the pump is then reset for another cycle.	Cell_Biology_Alberts. Humans have invented many different types of mechanical pumps, and it should not be surprising that cells also contain membrane-bound pumps that Figure 3–76 The abC (aTP-binding cassette) transporter, a protein machine that pumps molecules through a membrane. (A) How this large family of transporters pumps molecules into the cell in bacteria. As indicated, the binding of two molecules of ATP causes the two ATP-binding domains to clamp together tightly, opening a channel to the cell exterior. The binding of a substrate molecule to the extracellular face of the protein complex then triggers ATP hydrolysis followed by ADP release, which opens the cytoplasmic gate; the pump is then reset for another cycle.
Cell_Biology_Alberts_711	Cell_Biology_Alberts	(B) As discussed in Chapter 11, in eukaryotes an opposite process occurs, causing selected substrate molecules to be pumped out of the cell. (C) The structure of a bacterial ABC transporter (see Movie 11.5). (C, from R.J. Dawson and K.P. Locher, Nature 443:180–185, 2006. With permission from Macmillan Publishers Ltd; PDB code: 2HYD). function in other ways. Among the most notable are the rotary pumps that couple the hydrolysis of ATP to the transport of H+ ions (protons). These pumps resemble miniature turbines, and they are used to acidify the interior of lysosomes and other eukaryotic organelles. Like other ion pumps that create ion gradients, they can function in reverse to catalyze the reaction ADP + Pi → ATP, if the gradient across their membrane of the ion that they transport is steep enough.	Cell_Biology_Alberts. (B) As discussed in Chapter 11, in eukaryotes an opposite process occurs, causing selected substrate molecules to be pumped out of the cell. (C) The structure of a bacterial ABC transporter (see Movie 11.5). (C, from R.J. Dawson and K.P. Locher, Nature 443:180–185, 2006. With permission from Macmillan Publishers Ltd; PDB code: 2HYD). function in other ways. Among the most notable are the rotary pumps that couple the hydrolysis of ATP to the transport of H+ ions (protons). These pumps resemble miniature turbines, and they are used to acidify the interior of lysosomes and other eukaryotic organelles. Like other ion pumps that create ion gradients, they can function in reverse to catalyze the reaction ADP + Pi → ATP, if the gradient across their membrane of the ion that they transport is steep enough.
Cell_Biology_Alberts_712	Cell_Biology_Alberts	One such pump, the ATP synthase, harnesses a gradient of proton concentration produced by electron-transport processes to produce most of the ATP used in the living world. This ubiquitous pump has a central role in energy conversion, and we shall discuss its three-dimensional structure and mechanism in Chapter 14. Proteins Often Form Large Complexes That Function as Protein Machines	Cell_Biology_Alberts. One such pump, the ATP synthase, harnesses a gradient of proton concentration produced by electron-transport processes to produce most of the ATP used in the living world. This ubiquitous pump has a central role in energy conversion, and we shall discuss its three-dimensional structure and mechanism in Chapter 14. Proteins Often Form Large Complexes That Function as Protein Machines
Cell_Biology_Alberts_713	Cell_Biology_Alberts	Large proteins formed from many domains are able to perform more elaborate functions than small, single-domain proteins. But large protein assemblies formed from many protein molecules linked together by noncovalent bonds perform the most impressive tasks. Now that it is possible to reconstruct most biological processes in cell-free systems in the laboratory, it is clear that each of the central processes in a cell—such as DNA replication, protein synthesis, vesicle budding, or transmembrane signaling—is catalyzed by a highly coordinated, linked set of 10 or more proteins. In most such protein machines, an energetically favorable reaction such as the hydrolysis of bound nucleoside triphosphates (ATP or GTP) drives an ordered series of conformational changes in one or more of the individual protein subunits, enabling the ensemble of proteins to move coordinately. In this way, each enzyme can be moved directly into position, as the machine catalyzes successive reactions in a series	Cell_Biology_Alberts. Large proteins formed from many domains are able to perform more elaborate functions than small, single-domain proteins. But large protein assemblies formed from many protein molecules linked together by noncovalent bonds perform the most impressive tasks. Now that it is possible to reconstruct most biological processes in cell-free systems in the laboratory, it is clear that each of the central processes in a cell—such as DNA replication, protein synthesis, vesicle budding, or transmembrane signaling—is catalyzed by a highly coordinated, linked set of 10 or more proteins. In most such protein machines, an energetically favorable reaction such as the hydrolysis of bound nucleoside triphosphates (ATP or GTP) drives an ordered series of conformational changes in one or more of the individual protein subunits, enabling the ensemble of proteins to move coordinately. In this way, each enzyme can be moved directly into position, as the machine catalyzes successive reactions in a series
Cell_Biology_Alberts_714	Cell_Biology_Alberts	protein subunits, enabling the ensemble of proteins to move coordinately. In this way, each enzyme can be moved directly into position, as the machine catalyzes successive reactions in a series (Figure 3–77). This is what occurs, for example, in protein synthesis on a ribosome (discussed in Chapter 6)—or in DNA replication, where a large multiprotein complex moves rapidly along the DNA (discussed in Chapter 5).	Cell_Biology_Alberts. protein subunits, enabling the ensemble of proteins to move coordinately. In this way, each enzyme can be moved directly into position, as the machine catalyzes successive reactions in a series (Figure 3–77). This is what occurs, for example, in protein synthesis on a ribosome (discussed in Chapter 6)—or in DNA replication, where a large multiprotein complex moves rapidly along the DNA (discussed in Chapter 5).
Cell_Biology_Alberts_715	Cell_Biology_Alberts	Cells have evolved protein machines for the same reason that humans have invented mechanical and electronic machines. For accomplishing almost any task, manipulations that are spatially and temporally coordinated through linked processes are much more efficient than the use of many separate tools. Scaffolds Concentrate Sets of Interacting Proteins	Cell_Biology_Alberts. Cells have evolved protein machines for the same reason that humans have invented mechanical and electronic machines. For accomplishing almost any task, manipulations that are spatially and temporally coordinated through linked processes are much more efficient than the use of many separate tools. Scaffolds Concentrate Sets of Interacting Proteins
Cell_Biology_Alberts_716	Cell_Biology_Alberts	Scaffolds Concentrate Sets of Interacting Proteins As scientists have learned more of the details of cell biology, they have recognized an increasing degree of sophistication in cell chemistry. Thus, not only do we now know that protein machines play a predominant role, but it has also become clear that they are very often localized to specific sites in the cell, being assembled and activated only where and when they are needed. As one example, when extracellular signaling molecules bind to receptor proteins in the plasma membrane, the activated receptors often recruit a set of other proteins to the inside surface of the plasma membrane to form a large protein complex that passes the signal on (discussed in Chapter 15).	Cell_Biology_Alberts. Scaffolds Concentrate Sets of Interacting Proteins As scientists have learned more of the details of cell biology, they have recognized an increasing degree of sophistication in cell chemistry. Thus, not only do we now know that protein machines play a predominant role, but it has also become clear that they are very often localized to specific sites in the cell, being assembled and activated only where and when they are needed. As one example, when extracellular signaling molecules bind to receptor proteins in the plasma membrane, the activated receptors often recruit a set of other proteins to the inside surface of the plasma membrane to form a large protein complex that passes the signal on (discussed in Chapter 15).
Cell_Biology_Alberts_717	Cell_Biology_Alberts	The mechanisms frequently involve scaffold proteins. These are proteins with binding sites for multiple other proteins, and they serve both to link together specific sets of interacting proteins and to position them at specific locations inside a cell. At one extreme are rigid scaffolds, such as the cullin in SCF ubiquitin ligase (see Figure 3–71). At the other extreme are the large, flexible scaffold proteins that often underlie regions of specialized plasma membrane. These include the Figure 3–77 How “protein machines” carry out complex functions.	Cell_Biology_Alberts. The mechanisms frequently involve scaffold proteins. These are proteins with binding sites for multiple other proteins, and they serve both to link together specific sets of interacting proteins and to position them at specific locations inside a cell. At one extreme are rigid scaffolds, such as the cullin in SCF ubiquitin ligase (see Figure 3–71). At the other extreme are the large, flexible scaffold proteins that often underlie regions of specialized plasma membrane. These include the Figure 3–77 How “protein machines” carry out complex functions.
Cell_Biology_Alberts_718	Cell_Biology_Alberts	Figure 3–77 How “protein machines” carry out complex functions. These machines are made of individual proteins that collaborate to perform a specific task (Movie 3.13). The movement of these proteins is often coordinated by the hydrolysis of a bound nucleotide such as ATP or GTP. Directional allosteric conformational changes of proteins that are driven in this way often occur in a large protein assembly in which the activities of several different protein molecules are coordinated by such movements within the complex.	Cell_Biology_Alberts. Figure 3–77 How “protein machines” carry out complex functions. These machines are made of individual proteins that collaborate to perform a specific task (Movie 3.13). The movement of these proteins is often coordinated by the hydrolysis of a bound nucleotide such as ATP or GTP. Directional allosteric conformational changes of proteins that are driven in this way often occur in a large protein assembly in which the activities of several different protein molecules are coordinated by such movements within the complex.
Cell_Biology_Alberts_719	Cell_Biology_Alberts	Discs-large protein (Dlg), a protein of about 900 amino acids that is concentrated in special regions beneath the plasma membrane in epithelial cells and at synapses. Dlg contains binding sites for at least seven other proteins, interspersed with regions of more flexible polypeptide chain. An ancient protein, conserved in organisms as diverse as sponges, worms, flies, and humans, Dlg derives its name from the mutant phenotype of the organism in which it was first discovered; the cells in the imaginal discs of a Drosophila embryo with a mutation in the Dlg gene fail to stop proliferating when they should, and they produce unusually large discs whose epithelial cells can form tumors.	Cell_Biology_Alberts. Discs-large protein (Dlg), a protein of about 900 amino acids that is concentrated in special regions beneath the plasma membrane in epithelial cells and at synapses. Dlg contains binding sites for at least seven other proteins, interspersed with regions of more flexible polypeptide chain. An ancient protein, conserved in organisms as diverse as sponges, worms, flies, and humans, Dlg derives its name from the mutant phenotype of the organism in which it was first discovered; the cells in the imaginal discs of a Drosophila embryo with a mutation in the Dlg gene fail to stop proliferating when they should, and they produce unusually large discs whose epithelial cells can form tumors.
Cell_Biology_Alberts_720	Cell_Biology_Alberts	Although incompletely studied, Dlg and a large number of similar scaffold proteins are thought to function like the protein that is schematically illustrated in Figure 3–78. By binding a specific set of interacting proteins, these scaffolds can enhance the rate of critical reactions, while also confining them to the particular region of the cell that contains the scaffold. For similar reasons, cells also make extensive use of scaffold RNA molecules, as discussed in Chapter 7. Many Proteins Are Controlled by Covalent Modifications That Direct Them to Specific Sites Inside the Cell We have thus far described only a few ways in which proteins are post-translationally modified. A large number of other such modifications also occur, more than 200 distinct types being known. To give a sense of the variety, Table 3–3 presents	Cell_Biology_Alberts. Although incompletely studied, Dlg and a large number of similar scaffold proteins are thought to function like the protein that is schematically illustrated in Figure 3–78. By binding a specific set of interacting proteins, these scaffolds can enhance the rate of critical reactions, while also confining them to the particular region of the cell that contains the scaffold. For similar reasons, cells also make extensive use of scaffold RNA molecules, as discussed in Chapter 7. Many Proteins Are Controlled by Covalent Modifications That Direct Them to Specific Sites Inside the Cell We have thus far described only a few ways in which proteins are post-translationally modified. A large number of other such modifications also occur, more than 200 distinct types being known. To give a sense of the variety, Table 3–3 presents
Cell_Biology_Alberts_721	Cell_Biology_Alberts	Figure 3–78 How the proximity created by scaffold proteins can greatly speed reactions in a cell. In this example, long unstructured regions of polypeptide chain in a large scaffold protein connect a series of structured domains that bind a set of reacting proteins. The unstructured regions serve as flexible “tethers” that greatly speed reaction rates by causing a rapid, random collision of all of the proteins that are bound to the scaffold. (For specific examples of protein tethering, see Figure 3–54 and Figure 16–18; for scaffold RNA molecules, see Figure 7–49B.) a few of the modifying groups with known regulatory roles. As in phosphate and ubiquitin additions described previously, these groups are added and then removed from proteins according to the needs of the cell.	Cell_Biology_Alberts. Figure 3–78 How the proximity created by scaffold proteins can greatly speed reactions in a cell. In this example, long unstructured regions of polypeptide chain in a large scaffold protein connect a series of structured domains that bind a set of reacting proteins. The unstructured regions serve as flexible “tethers” that greatly speed reaction rates by causing a rapid, random collision of all of the proteins that are bound to the scaffold. (For specific examples of protein tethering, see Figure 3–54 and Figure 16–18; for scaffold RNA molecules, see Figure 7–49B.) a few of the modifying groups with known regulatory roles. As in phosphate and ubiquitin additions described previously, these groups are added and then removed from proteins according to the needs of the cell.
Cell_Biology_Alberts_722	Cell_Biology_Alberts	A large number of proteins are now known to be modified on more than one amino acid side chain, with different regulatory events producing a different pattern of such modifications. A striking example is the protein p53, which plays a central part in controlling a cell’s response to adverse circumstances (see Figure 17–62). Through one of four different types of molecular additions, this protein can be modified at 20 different sites. Because an enormous number of different combinations of these 20 modifications are possible, the protein’s behavior can in principle be altered in a huge number of ways. Such modifications will often create a site on the modified protein that binds it to a scaffold protein in a specific region of the cell, thereby connecting it—via the scaffold—to the other proteins required for a reaction at that site.	Cell_Biology_Alberts. A large number of proteins are now known to be modified on more than one amino acid side chain, with different regulatory events producing a different pattern of such modifications. A striking example is the protein p53, which plays a central part in controlling a cell’s response to adverse circumstances (see Figure 17–62). Through one of four different types of molecular additions, this protein can be modified at 20 different sites. Because an enormous number of different combinations of these 20 modifications are possible, the protein’s behavior can in principle be altered in a huge number of ways. Such modifications will often create a site on the modified protein that binds it to a scaffold protein in a specific region of the cell, thereby connecting it—via the scaffold—to the other proteins required for a reaction at that site.
Cell_Biology_Alberts_723	Cell_Biology_Alberts	One can view each protein’s set of covalent modifications as a combinatorial regulatory code. Specific modifying groups are added to or removed from a protein in response to signals, and the code then alters protein behavior—changing the activity or stability of the protein, its binding partners, and/or its specific location within the cell (Figure 3–79). As a result, the cell is able to respond rapidly and with great versatility to changes in its condition or environment. A Complex Network of Protein Interactions Underlies Cell Function	Cell_Biology_Alberts. One can view each protein’s set of covalent modifications as a combinatorial regulatory code. Specific modifying groups are added to or removed from a protein in response to signals, and the code then alters protein behavior—changing the activity or stability of the protein, its binding partners, and/or its specific location within the cell (Figure 3–79). As a result, the cell is able to respond rapidly and with great versatility to changes in its condition or environment. A Complex Network of Protein Interactions Underlies Cell Function
Cell_Biology_Alberts_724	Cell_Biology_Alberts	A Complex Network of Protein Interactions Underlies Cell Function There are many challenges facing cell biologists in this information-rich era when a large number of complete genome sequences are known. One is the need to dissect and reconstruct each one of the thousands of protein machines that exist in an organism such as ourselves. To understand these remarkable protein complexes, each will need to be reconstituted from its purified protein parts, so that we can study its detailed mode of operation under controlled conditions in a test tube, free from all other cell components. This alone is a massive task. But we now know that each of these subcomponents of a cell also interacts with other sets of macromolecules, creating a large network of protein–protein and protein–nucleic acid interactions throughout the cell. To understand the cell, therefore, we will need to analyze most of these other interactions as well.	Cell_Biology_Alberts. A Complex Network of Protein Interactions Underlies Cell Function There are many challenges facing cell biologists in this information-rich era when a large number of complete genome sequences are known. One is the need to dissect and reconstruct each one of the thousands of protein machines that exist in an organism such as ourselves. To understand these remarkable protein complexes, each will need to be reconstituted from its purified protein parts, so that we can study its detailed mode of operation under controlled conditions in a test tube, free from all other cell components. This alone is a massive task. But we now know that each of these subcomponents of a cell also interacts with other sets of macromolecules, creating a large network of protein–protein and protein–nucleic acid interactions throughout the cell. To understand the cell, therefore, we will need to analyze most of these other interactions as well.
Cell_Biology_Alberts_725	Cell_Biology_Alberts	Figure 3–79 Multisite protein modification and its effects. (A) A protein that carries a post-translational addition to more than one of its amino acid side chains can be considered to carry a combinatorial regulatory code. Multisite modifications are added to (and removed from) a protein through signaling networks, and the resulting combinatorial regulatory code on the protein is read to alter its behavior in the cell. (B) The pattern of some covalent modifications to the protein p53. We can gain some idea of the complexity of intracellular protein networks from a particularly well-studied example described in Chapter 16: the many dozens of proteins that interact with the actin cytoskeleton to control actin filament behavior (see Panel 16–3, p. 905).	Cell_Biology_Alberts. Figure 3–79 Multisite protein modification and its effects. (A) A protein that carries a post-translational addition to more than one of its amino acid side chains can be considered to carry a combinatorial regulatory code. Multisite modifications are added to (and removed from) a protein through signaling networks, and the resulting combinatorial regulatory code on the protein is read to alter its behavior in the cell. (B) The pattern of some covalent modifications to the protein p53. We can gain some idea of the complexity of intracellular protein networks from a particularly well-studied example described in Chapter 16: the many dozens of proteins that interact with the actin cytoskeleton to control actin filament behavior (see Panel 16–3, p. 905).
Cell_Biology_Alberts_726	Cell_Biology_Alberts	The extent of such protein–protein interactions can also be estimated more generally. An enormous amount of valuable information is now freely available in protein databases on the Internet: tens of thousands of three-dimensional protein structures plus tens of millions of protein sequences derived from the nucleotide sequences of genes. Scientists have been developing new methods for mining this great resource to increase our understanding of cells. In particular, computer-based bioinformatics tools are being combined with robotics and other technologies to allow thousands of proteins to be investigated in a single set of experiments. Proteomics is a term that is often used to describe such research focused on the analysis of large sets of proteins, analogous to the term genomics describing the large-scale analysis of DNA sequences and genes.	Cell_Biology_Alberts. The extent of such protein–protein interactions can also be estimated more generally. An enormous amount of valuable information is now freely available in protein databases on the Internet: tens of thousands of three-dimensional protein structures plus tens of millions of protein sequences derived from the nucleotide sequences of genes. Scientists have been developing new methods for mining this great resource to increase our understanding of cells. In particular, computer-based bioinformatics tools are being combined with robotics and other technologies to allow thousands of proteins to be investigated in a single set of experiments. Proteomics is a term that is often used to describe such research focused on the analysis of large sets of proteins, analogous to the term genomics describing the large-scale analysis of DNA sequences and genes.
Cell_Biology_Alberts_727	Cell_Biology_Alberts	A biochemical method based on affinity tagging and mass spectroscopy has proven especially powerful for determining the direct binding interactions between the many different proteins in a cell (discussed in Chapter 8). The results are being tabulated and organized in Internet databases. This allows a cell biologist studying a small set of proteins to readily discover which other proteins in the same cell are likely to bind to, and thus interact with, that set of proteins. When displayed graphically as a protein interaction map, each protein is represented by a box or dot in a two-dimensional network, with a straight line connecting those proteins that have been found to bind to each other.	Cell_Biology_Alberts. A biochemical method based on affinity tagging and mass spectroscopy has proven especially powerful for determining the direct binding interactions between the many different proteins in a cell (discussed in Chapter 8). The results are being tabulated and organized in Internet databases. This allows a cell biologist studying a small set of proteins to readily discover which other proteins in the same cell are likely to bind to, and thus interact with, that set of proteins. When displayed graphically as a protein interaction map, each protein is represented by a box or dot in a two-dimensional network, with a straight line connecting those proteins that have been found to bind to each other.
Cell_Biology_Alberts_728	Cell_Biology_Alberts	When hundreds or thousands of proteins are displayed on the same map, the network diagram becomes bewilderingly complicated, serving to illustrate the enormous challenges that face scientists attempting to understand the cell (Figure 3–80). Much more useful are small subsections of these maps, centered on a few proteins of interest.	Cell_Biology_Alberts. When hundreds or thousands of proteins are displayed on the same map, the network diagram becomes bewilderingly complicated, serving to illustrate the enormous challenges that face scientists attempting to understand the cell (Figure 3–80). Much more useful are small subsections of these maps, centered on a few proteins of interest.
Cell_Biology_Alberts_729	Cell_Biology_Alberts	We have previously described the structure and mode of action of the SCF ubiquitin ligase, using it to illustrate how protein complexes are constructed from interchangeable parts (see Figure 3–71). Figure 3–81 shows a network of protein– protein interactions for the five proteins that form this protein complex in a yeast cell. Four of the subunits of this ligase are located at the bottom right of this figure. The remaining subunit, the F-box protein that serves as its substrate-binding arm, appears as a set of 15 different gene products that bind to adaptor protein 2 (the Skp1 protein). Along the top and left of the figure are sets of additional protein interactions marked with yellow and green shading: as indicated, these protein sets function at the origin of DNA replication, in cell cycle regulation, in methionine synthesis, in the kinetochore, and in vacuolar H+-ATPase assembly. We shall use this figure to explain how such protein interaction maps are used, and what they do and do	Cell_Biology_Alberts. We have previously described the structure and mode of action of the SCF ubiquitin ligase, using it to illustrate how protein complexes are constructed from interchangeable parts (see Figure 3–71). Figure 3–81 shows a network of protein– protein interactions for the five proteins that form this protein complex in a yeast cell. Four of the subunits of this ligase are located at the bottom right of this figure. The remaining subunit, the F-box protein that serves as its substrate-binding arm, appears as a set of 15 different gene products that bind to adaptor protein 2 (the Skp1 protein). Along the top and left of the figure are sets of additional protein interactions marked with yellow and green shading: as indicated, these protein sets function at the origin of DNA replication, in cell cycle regulation, in methionine synthesis, in the kinetochore, and in vacuolar H+-ATPase assembly. We shall use this figure to explain how such protein interaction maps are used, and what they do and do
Cell_Biology_Alberts_730	Cell_Biology_Alberts	regulation, in methionine synthesis, in the kinetochore, and in vacuolar H+-ATPase assembly. We shall use this figure to explain how such protein interaction maps are used, and what they do and do not mean.	Cell_Biology_Alberts. regulation, in methionine synthesis, in the kinetochore, and in vacuolar H+-ATPase assembly. We shall use this figure to explain how such protein interaction maps are used, and what they do and do not mean.
Cell_Biology_Alberts_731	Cell_Biology_Alberts	1. Protein interaction maps are useful for identifying the likely function of previously uncharacterized proteins. Examples are the products of the genes that have thus far only been inferred to exist from the yeast genome sequence, which are the three proteins in the figure that lack a simple three-letter abbreviation (white letters beginning with Y). The three in this diagram are F-box proteins that bind to Skp1; these are therefore likely to function as part of the ubiquitin ligase, serving as substrate-binding arms that recognize different target proteins. However, as we discuss next, neither assignment can be considered certain without additional data. 2.	Cell_Biology_Alberts. 1. Protein interaction maps are useful for identifying the likely function of previously uncharacterized proteins. Examples are the products of the genes that have thus far only been inferred to exist from the yeast genome sequence, which are the three proteins in the figure that lack a simple three-letter abbreviation (white letters beginning with Y). The three in this diagram are F-box proteins that bind to Skp1; these are therefore likely to function as part of the ubiquitin ligase, serving as substrate-binding arms that recognize different target proteins. However, as we discuss next, neither assignment can be considered certain without additional data. 2.
Cell_Biology_Alberts_732	Cell_Biology_Alberts	2. Protein interaction networks need to be interpreted with caution because, as a result of evolution making efficient use of each organism’s genetic information, the same protein can be used as part of different protein complexes that have different types of functions. Thus, although protein A binds to protein B and protein B binds to protein C, proteins A and C need not function in the same process. For example, we know from detailed biochemical studies that the functions of Skp1 in the kinetochore and in Figure 3–80 a network of protein-binding interactions in a yeast cell. Each line connecting a pair of dots (proteins) indicates a protein–protein interaction. (From A. Guimerá and M. Sales–Pardo, Mol. Syst. Biol. 2:42, 2006. With permission from Macmillan Publishers Ltd.) Figure 3–81 a map of some protein–protein interactions of the SCF ubiquitin ligase and other proteins in the yeast	Cell_Biology_Alberts. 2. Protein interaction networks need to be interpreted with caution because, as a result of evolution making efficient use of each organism’s genetic information, the same protein can be used as part of different protein complexes that have different types of functions. Thus, although protein A binds to protein B and protein B binds to protein C, proteins A and C need not function in the same process. For example, we know from detailed biochemical studies that the functions of Skp1 in the kinetochore and in Figure 3–80 a network of protein-binding interactions in a yeast cell. Each line connecting a pair of dots (proteins) indicates a protein–protein interaction. (From A. Guimerá and M. Sales–Pardo, Mol. Syst. Biol. 2:42, 2006. With permission from Macmillan Publishers Ltd.) Figure 3–81 a map of some protein–protein interactions of the SCF ubiquitin ligase and other proteins in the yeast
Cell_Biology_Alberts_733	Cell_Biology_Alberts	Figure 3–81 a map of some protein–protein interactions of the SCF ubiquitin ligase and other proteins in the yeast S. cerevisiae. The symbols and/or colors used for the five proteins of the ligase are those in Figure 3–71. Note that 15 different F-box proteins are shown (purple); those with white lettering (beginning with Y) are known from the genome sequence as open reading frames. For additional details, see text. (Courtesy of Peter Bowers and David Eisenberg, UCLA-DOE Institute for Genomics and Proteomics, UCLA.) vacuolar H+-ATPase assembly (yellow shading) are separate from its function in the SCF ubiquitin ligase. In fact, only the remaining three functions of Skp1 illustrated in the diagram—methionine synthesis, cell cycle regulation, and origin of replication (green shading)—involve ubiquitylation.	Cell_Biology_Alberts. Figure 3–81 a map of some protein–protein interactions of the SCF ubiquitin ligase and other proteins in the yeast S. cerevisiae. The symbols and/or colors used for the five proteins of the ligase are those in Figure 3–71. Note that 15 different F-box proteins are shown (purple); those with white lettering (beginning with Y) are known from the genome sequence as open reading frames. For additional details, see text. (Courtesy of Peter Bowers and David Eisenberg, UCLA-DOE Institute for Genomics and Proteomics, UCLA.) vacuolar H+-ATPase assembly (yellow shading) are separate from its function in the SCF ubiquitin ligase. In fact, only the remaining three functions of Skp1 illustrated in the diagram—methionine synthesis, cell cycle regulation, and origin of replication (green shading)—involve ubiquitylation.
Cell_Biology_Alberts_734	Cell_Biology_Alberts	3. In cross-species comparisons, those proteins displaying similar patterns of interactions in the two protein interaction maps are likely to have the same function in the cell. Thus, as scientists generate more and more highly detailed maps for multiple organisms, the results will become increasingly useful for inferring protein function. These map comparisons will be a particularly powerful tool for deciphering the functions of human proteins, because a vast amount of direct information about protein function can be obtained from genetic engineering, mutational, and genetic analyses in experimental organisms—such as yeast, worms, and flies—that are not feasible in humans.	Cell_Biology_Alberts. 3. In cross-species comparisons, those proteins displaying similar patterns of interactions in the two protein interaction maps are likely to have the same function in the cell. Thus, as scientists generate more and more highly detailed maps for multiple organisms, the results will become increasingly useful for inferring protein function. These map comparisons will be a particularly powerful tool for deciphering the functions of human proteins, because a vast amount of direct information about protein function can be obtained from genetic engineering, mutational, and genetic analyses in experimental organisms—such as yeast, worms, and flies—that are not feasible in humans.
Cell_Biology_Alberts_735	Cell_Biology_Alberts	What does the future hold? There are likely to be on the order of 10,000 different proteins in a typical human cell, each of which interacts with 5 to 10 different partners. Despite the enormous progress made in recent years, we cannot yet claim to understand even the simplest known cells, such as the small Mycoplasma bacterium formed from only about 500 gene products (see Figure 1–10). How then can we hope to understand a human? Clearly, a great deal of new biochemistry will be essential, in which each protein in a particular interacting set is purified so that its chemistry and interactions can be dissected in a test tube. But in addition, more powerful ways of analyzing networks will be needed based on mathematical and computational tools not yet invented, as we shall emphasize in Chapter 8. Clearly, there are many wonderful challenges that remain for future generations of cell biologists.	Cell_Biology_Alberts. What does the future hold? There are likely to be on the order of 10,000 different proteins in a typical human cell, each of which interacts with 5 to 10 different partners. Despite the enormous progress made in recent years, we cannot yet claim to understand even the simplest known cells, such as the small Mycoplasma bacterium formed from only about 500 gene products (see Figure 1–10). How then can we hope to understand a human? Clearly, a great deal of new biochemistry will be essential, in which each protein in a particular interacting set is purified so that its chemistry and interactions can be dissected in a test tube. But in addition, more powerful ways of analyzing networks will be needed based on mathematical and computational tools not yet invented, as we shall emphasize in Chapter 8. Clearly, there are many wonderful challenges that remain for future generations of cell biologists.
Cell_Biology_Alberts_736	Cell_Biology_Alberts	Proteins can form enormously sophisticated chemical devices, whose functions largely depend on the detailed chemical properties of their surfaces. Binding sites for ligands are formed as surface cavities in which precisely positioned amino acid side chains are brought together by protein folding. In this way, normally unreactive amino acid side chains can be activated to make and break covalent bonds. Enzymes are catalytic proteins that greatly speed up reaction rates by binding the high-energy transition states for a specific reaction path; they also can perform acid catalysis and base catalysis simultaneously. The rates of enzyme reactions are often so fast that they are limited only by diffusion. Rates can be further increased only if enzymes that act sequentially on a substrate are joined into a single multienzyme complex, or if the enzymes and their substrates are attached to protein scaffolds, or otherwise confined to the same part of the cell.	Cell_Biology_Alberts. Proteins can form enormously sophisticated chemical devices, whose functions largely depend on the detailed chemical properties of their surfaces. Binding sites for ligands are formed as surface cavities in which precisely positioned amino acid side chains are brought together by protein folding. In this way, normally unreactive amino acid side chains can be activated to make and break covalent bonds. Enzymes are catalytic proteins that greatly speed up reaction rates by binding the high-energy transition states for a specific reaction path; they also can perform acid catalysis and base catalysis simultaneously. The rates of enzyme reactions are often so fast that they are limited only by diffusion. Rates can be further increased only if enzymes that act sequentially on a substrate are joined into a single multienzyme complex, or if the enzymes and their substrates are attached to protein scaffolds, or otherwise confined to the same part of the cell.
Cell_Biology_Alberts_737	Cell_Biology_Alberts	Proteins reversibly change their shape when ligands bind to their surface. The allosteric changes in protein conformation produced by one ligand affect the binding of a second ligand, and this linkage between two ligand-binding sites provides a crucial mechanism for regulating cell processes. Metabolic pathways, for example, are controlled by feedback regulation: some small molecules inhibit and other small molecules activate enzymes early in a pathway. Enzymes controlled in this way generally form symmetric assemblies, allowing cooperative conformational changes to create a steep response to changes in the concentrations of the ligands that regulate them.	Cell_Biology_Alberts. Proteins reversibly change their shape when ligands bind to their surface. The allosteric changes in protein conformation produced by one ligand affect the binding of a second ligand, and this linkage between two ligand-binding sites provides a crucial mechanism for regulating cell processes. Metabolic pathways, for example, are controlled by feedback regulation: some small molecules inhibit and other small molecules activate enzymes early in a pathway. Enzymes controlled in this way generally form symmetric assemblies, allowing cooperative conformational changes to create a steep response to changes in the concentrations of the ligands that regulate them.
Cell_Biology_Alberts_738	Cell_Biology_Alberts	The expenditure of chemical energy can drive unidirectional changes in protein shape. By coupling allosteric shape changes to ATP hydrolysis, for example, proteins can do useful work, such as generating a mechanical force or moving for long distances in a single direction. The three-dimensional structures of proteins have revealed how a small local change caused by nucleoside triphosphate hydrolysis is amplified to create major changes elsewhere in the protein. By such means, these proteins can serve as input–output devices that transmit information, as assembly factors, as motors, or as membrane-bound pumps. Highly efficient protein machines are formed by incorporating many different protein molecules into larger assemblies that coordinate the allosteric movements of the individual components. Such machines perform most of the important reactions in cells.	Cell_Biology_Alberts. The expenditure of chemical energy can drive unidirectional changes in protein shape. By coupling allosteric shape changes to ATP hydrolysis, for example, proteins can do useful work, such as generating a mechanical force or moving for long distances in a single direction. The three-dimensional structures of proteins have revealed how a small local change caused by nucleoside triphosphate hydrolysis is amplified to create major changes elsewhere in the protein. By such means, these proteins can serve as input–output devices that transmit information, as assembly factors, as motors, or as membrane-bound pumps. Highly efficient protein machines are formed by incorporating many different protein molecules into larger assemblies that coordinate the allosteric movements of the individual components. Such machines perform most of the important reactions in cells.
Cell_Biology_Alberts_739	Cell_Biology_Alberts	Proteins are subjected to many reversible, post-translational modifications, such as the covalent addition of a phosphate or an acetyl group to a specific amino acid side chain. The addition of these modifying groups is used to regulate the activity of a protein, changing its conformation, its binding to other proteins, and its location inside the cell. A typical protein in a cell will interact with more than five different partners. Through proteomics, biologists can analyze thousands of proteins in one set of experiments. One important result is the production of detailed protein interaction maps, which aim at describing all of the binding interactions between the thousands of distinct proteins in a cell. However, understanding these networks will require new biochemistry, through which small sets of interacting proteins can be purified and their chemistry dissected in detail. In addition, new computational techniques will be required to deal with the enormous complexity.	Cell_Biology_Alberts. Proteins are subjected to many reversible, post-translational modifications, such as the covalent addition of a phosphate or an acetyl group to a specific amino acid side chain. The addition of these modifying groups is used to regulate the activity of a protein, changing its conformation, its binding to other proteins, and its location inside the cell. A typical protein in a cell will interact with more than five different partners. Through proteomics, biologists can analyze thousands of proteins in one set of experiments. One important result is the production of detailed protein interaction maps, which aim at describing all of the binding interactions between the thousands of distinct proteins in a cell. However, understanding these networks will require new biochemistry, through which small sets of interacting proteins can be purified and their chemistry dissected in detail. In addition, new computational techniques will be required to deal with the enormous complexity.
Cell_Biology_Alberts_740	Cell_Biology_Alberts	What are the functions of the surprisingly large amount of unfolded polypeptide chain found in proteins? How many types of protein functions remain to be discovered? What are the most promising approaches for discovering them? When will scientists be able to take any amino acid sequence and accurately predict both that protein’s three-dimensional conformations and its chemical properties? What breakthroughs will be needed to accomplish this important goal? Are there ways to reveal the detailed workings of a protein machine that do not require the purification of each of its component parts in large amounts, so that the machine’s functions can be reconstituted and dissected using chemical techniques in a test tube? What are the roles of the dozens of different types of covalent modifications of proteins that have been found in addition to those listed in Table 3–3? Which ones are critical for cell function and why?	Cell_Biology_Alberts. What are the functions of the surprisingly large amount of unfolded polypeptide chain found in proteins? How many types of protein functions remain to be discovered? What are the most promising approaches for discovering them? When will scientists be able to take any amino acid sequence and accurately predict both that protein’s three-dimensional conformations and its chemical properties? What breakthroughs will be needed to accomplish this important goal? Are there ways to reveal the detailed workings of a protein machine that do not require the purification of each of its component parts in large amounts, so that the machine’s functions can be reconstituted and dissected using chemical techniques in a test tube? What are the roles of the dozens of different types of covalent modifications of proteins that have been found in addition to those listed in Table 3–3? Which ones are critical for cell function and why?
Cell_Biology_Alberts_741	Cell_Biology_Alberts	Why is amyloid toxic to cells and how does it contribute to neurodegenerative diseases such as Alzheimer’s disease? Which statements are true? explain why or why not. 3–1 Each strand in a β sheet is a helix with two amino acids per turn. 3–2 Intrinsically disordered regions of proteins can be identified using bioinformatic methods to search genes for encoded amino acid sequences that possess high hydrophobicity and low net charge. 3–3 Loops of polypeptide that protrude from the surface of a protein often form the binding sites for other molecules. 3–4 An enzyme reaches a maximum rate at high substrate concentration because it has a fixed number of active sites where substrate binds. 3–5 Higher concentrations of enzyme give rise to a higher turnover number. 3–6 Enzymes that undergo cooperative allosteric transitions invariably consist of symmetric assemblies of multiple subunits.	Cell_Biology_Alberts. Why is amyloid toxic to cells and how does it contribute to neurodegenerative diseases such as Alzheimer’s disease? Which statements are true? explain why or why not. 3–1 Each strand in a β sheet is a helix with two amino acids per turn. 3–2 Intrinsically disordered regions of proteins can be identified using bioinformatic methods to search genes for encoded amino acid sequences that possess high hydrophobicity and low net charge. 3–3 Loops of polypeptide that protrude from the surface of a protein often form the binding sites for other molecules. 3–4 An enzyme reaches a maximum rate at high substrate concentration because it has a fixed number of active sites where substrate binds. 3–5 Higher concentrations of enzyme give rise to a higher turnover number. 3–6 Enzymes that undergo cooperative allosteric transitions invariably consist of symmetric assemblies of multiple subunits.
Cell_Biology_Alberts_742	Cell_Biology_Alberts	3–6 Enzymes that undergo cooperative allosteric transitions invariably consist of symmetric assemblies of multiple subunits. 3–7 Continual addition and removal of phosphates by protein kinases and protein phosphatases is wasteful of energy—since their combined action consumes ATP— but it is a necessary consequence of effective regulation by phosphorylation. Discuss the following problems.	Cell_Biology_Alberts. 3–6 Enzymes that undergo cooperative allosteric transitions invariably consist of symmetric assemblies of multiple subunits. 3–7 Continual addition and removal of phosphates by protein kinases and protein phosphatases is wasteful of energy—since their combined action consumes ATP— but it is a necessary consequence of effective regulation by phosphorylation. Discuss the following problems.
Cell_Biology_Alberts_743	Cell_Biology_Alberts	Discuss the following problems. 3–8 Consider the following statement. “To produce one molecule of each possible kind of polypeptide chain, 300 amino acids in length, would require more atoms than exist in the universe.” Given the size of the universe, do you suppose this statement could possibly be correct? Since counting atoms is a tricky business, consider the problem from the standpoint of mass. The mass of the observable universe is estimated to be about 1080 grams, give or take an order of magnitude or so. Assuming that the average One such kelch repeat domain is shown in Figure Q3–1. Would you classify this domain as an “in-line” or “plug-in” type domain? ˜7 Figure Q3–1 The kelch repeat domain of D. dendroides (Problem 3–10). The seven individual β propellers are color coded and labeled. The Nand C-termini are indicated by N and C.	Cell_Biology_Alberts. Discuss the following problems. 3–8 Consider the following statement. “To produce one molecule of each possible kind of polypeptide chain, 300 amino acids in length, would require more atoms than exist in the universe.” Given the size of the universe, do you suppose this statement could possibly be correct? Since counting atoms is a tricky business, consider the problem from the standpoint of mass. The mass of the observable universe is estimated to be about 1080 grams, give or take an order of magnitude or so. Assuming that the average One such kelch repeat domain is shown in Figure Q3–1. Would you classify this domain as an “in-line” or “plug-in” type domain? ˜7 Figure Q3–1 The kelch repeat domain of D. dendroides (Problem 3–10). The seven individual β propellers are color coded and labeled. The Nand C-termini are indicated by N and C.
Cell_Biology_Alberts_744	Cell_Biology_Alberts	˜7 Figure Q3–1 The kelch repeat domain of D. dendroides (Problem 3–10). The seven individual β propellers are color coded and labeled. The Nand C-termini are indicated by N and C. 3–11 Titin, which has a molecular weight of about 3 × 106, is the largest polypeptide yet described. Titin molecules extend from muscle thick filaments to the Z disc; they are thought to act as springs to keep the thick filaments centered in the sarcomere. Titin is composed of a large number of repeated immunoglobulin (Ig) sequences of 89 amino acids, each of which is folded into a domain about 4 nm in length (Figure Q3–2A).	Cell_Biology_Alberts. ˜7 Figure Q3–1 The kelch repeat domain of D. dendroides (Problem 3–10). The seven individual β propellers are color coded and labeled. The Nand C-termini are indicated by N and C. 3–11 Titin, which has a molecular weight of about 3 × 106, is the largest polypeptide yet described. Titin molecules extend from muscle thick filaments to the Z disc; they are thought to act as springs to keep the thick filaments centered in the sarcomere. Titin is composed of a large number of repeated immunoglobulin (Ig) sequences of 89 amino acids, each of which is folded into a domain about 4 nm in length (Figure Q3–2A).
Cell_Biology_Alberts_745	Cell_Biology_Alberts	You suspect that the springlike behavior of titin is caused by the sequential unfolding (and refolding) of individual Ig domains. You test this hypothesis using the atomic force microscope, which allows you to pick up one end of a protein molecule and pull with an accurately measured force. For a fragment of titin containing seven repeats of the Ig domain, this experiment gives the sawtooth force-versus-extension curve shown in Figure Q3–2B. If the experiment is repeated in a solution of 8 M urea (a protein denaturant), the peaks disappear and the measured extension becomes much longer for a given force. If the experiment is repeated after the protein has been cross-linked by treatment with glutaraldehyde, once again the peaks disappear but the extension becomes much smaller for a given force.	Cell_Biology_Alberts. You suspect that the springlike behavior of titin is caused by the sequential unfolding (and refolding) of individual Ig domains. You test this hypothesis using the atomic force microscope, which allows you to pick up one end of a protein molecule and pull with an accurately measured force. For a fragment of titin containing seven repeats of the Ig domain, this experiment gives the sawtooth force-versus-extension curve shown in Figure Q3–2B. If the experiment is repeated in a solution of 8 M urea (a protein denaturant), the peaks disappear and the measured extension becomes much longer for a given force. If the experiment is repeated after the protein has been cross-linked by treatment with glutaraldehyde, once again the peaks disappear but the extension becomes much smaller for a given force.
Cell_Biology_Alberts_746	Cell_Biology_Alberts	mass of an amino acid is 110 daltons, what would be the mass of one molecule of each possible kind of polypeptide chain 300 amino acids in length? Is this greater than the mass of the universe? homologous proteins is to search the database using a short signature sequence indicative of the particular protein function. Why is it better to search with a short sequence than with a long sequence? Do you not have more chances 0 for a “hit” in the database with a long sequence? 3–10 The so-called kelch motif consists of a four-stranded β sheet, which forms what is known as a β pro- Figure Q3–2 Springlike behavior of titin (Problem 3–11). (A) The peller. It is usually found to be repeated four to seven times, structure of an individual Ig domain. (B) Force in piconewtons versus forming a kelch repeat domain in a multidomain protein. extension in nanometers obtained by atomic force microscopy. a.	Cell_Biology_Alberts. mass of an amino acid is 110 daltons, what would be the mass of one molecule of each possible kind of polypeptide chain 300 amino acids in length? Is this greater than the mass of the universe? homologous proteins is to search the database using a short signature sequence indicative of the particular protein function. Why is it better to search with a short sequence than with a long sequence? Do you not have more chances 0 for a “hit” in the database with a long sequence? 3–10 The so-called kelch motif consists of a four-stranded β sheet, which forms what is known as a β pro- Figure Q3–2 Springlike behavior of titin (Problem 3–11). (A) The peller. It is usually found to be repeated four to seven times, structure of an individual Ig domain. (B) Force in piconewtons versus forming a kelch repeat domain in a multidomain protein. extension in nanometers obtained by atomic force microscopy. a.
Cell_Biology_Alberts_747	Cell_Biology_Alberts	a. Are the data consistent with your hypothesis that titin’s springlike behavior is due to the sequential unfolding of individual Ig domains? Explain your reasoning. b. Is the extension for each putative domain-unfolding event the magnitude you would expect? (In an extended polypeptide chain, amino acids are spaced at intervals of 0.34 nm.) C. Why is each successive peak in Figure Q3–2B a little higher than the one before? D. Why does the force collapse so abruptly after each peak?	Cell_Biology_Alberts. a. Are the data consistent with your hypothesis that titin’s springlike behavior is due to the sequential unfolding of individual Ig domains? Explain your reasoning. b. Is the extension for each putative domain-unfolding event the magnitude you would expect? (In an extended polypeptide chain, amino acids are spaced at intervals of 0.34 nm.) C. Why is each successive peak in Figure Q3–2B a little higher than the one before? D. Why does the force collapse so abruptly after each peak?
Cell_Biology_Alberts_748	Cell_Biology_Alberts	C. Why is each successive peak in Figure Q3–2B a little higher than the one before? D. Why does the force collapse so abruptly after each peak? 3–12 Rous sarcoma virus (RSV) carries an oncogene called Src, which encodes a continuously active protein tyrosine kinase that leads to unchecked cell proliferation. Normally, Src carries an attached fatty acid (myristoylate) group that allows it to bind to the cytoplasmic side of the plasma membrane. A mutant version of Src that does not allow attachment of myristoylate does not bind to the membrane. Infection of cells with RSV encoding either the normal or the mutant form of Src leads to the same high level of protein tyrosine kinase activity, but the mutant Src does not cause cell proliferation. a.	Cell_Biology_Alberts. C. Why is each successive peak in Figure Q3–2B a little higher than the one before? D. Why does the force collapse so abruptly after each peak? 3–12 Rous sarcoma virus (RSV) carries an oncogene called Src, which encodes a continuously active protein tyrosine kinase that leads to unchecked cell proliferation. Normally, Src carries an attached fatty acid (myristoylate) group that allows it to bind to the cytoplasmic side of the plasma membrane. A mutant version of Src that does not allow attachment of myristoylate does not bind to the membrane. Infection of cells with RSV encoding either the normal or the mutant form of Src leads to the same high level of protein tyrosine kinase activity, but the mutant Src does not cause cell proliferation. a.
Cell_Biology_Alberts_749	Cell_Biology_Alberts	a. Assuming that the normal Src is all bound to the plasma membrane and that the mutant Src is distributed throughout the cytoplasm, calculate their relative concentrations in the neighborhood of the plasma membrane. For the purposes of this calculation, assume that the cell is a sphere with a radius (r) of 10 μm and that the mutant Src is distributed throughout the cell, whereas the normal Src is confined to a 4-nm-thick layer immediately beneath the membrane. [For this problem, assume that the membrane has no thickness. The volume of a sphere is (4/3)πr3.] b. The target (X) for phosphorylation by Src resides in the membrane. Explain why the mutant Src does not cause cell proliferation.	Cell_Biology_Alberts. a. Assuming that the normal Src is all bound to the plasma membrane and that the mutant Src is distributed throughout the cytoplasm, calculate their relative concentrations in the neighborhood of the plasma membrane. For the purposes of this calculation, assume that the cell is a sphere with a radius (r) of 10 μm and that the mutant Src is distributed throughout the cell, whereas the normal Src is confined to a 4-nm-thick layer immediately beneath the membrane. [For this problem, assume that the membrane has no thickness. The volume of a sphere is (4/3)πr3.] b. The target (X) for phosphorylation by Src resides in the membrane. Explain why the mutant Src does not cause cell proliferation.