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Cell_Biology_Alberts_510	Cell_Biology_Alberts	The same weak noncovalent bonds that enable a protein chain to fold into a specific conformation also allow proteins to bind to each other to produce larger structures in the cell. Any region of a protein’s surface that can interact with another molecule through sets of noncovalent bonds is called a binding site. A protein can contain binding sites for various large and small molecules. If a binding site recognizes the surface of a second protein, the tight binding of two folded polypeptide chains at this site creates a larger protein molecule with a precisely defined geometry. Each polypeptide chain in such a protein is called a protein subunit.	Cell_Biology_Alberts. The same weak noncovalent bonds that enable a protein chain to fold into a specific conformation also allow proteins to bind to each other to produce larger structures in the cell. Any region of a protein’s surface that can interact with another molecule through sets of noncovalent bonds is called a binding site. A protein can contain binding sites for various large and small molecules. If a binding site recognizes the surface of a second protein, the tight binding of two folded polypeptide chains at this site creates a larger protein molecule with a precisely defined geometry. Each polypeptide chain in such a protein is called a protein subunit.
Cell_Biology_Alberts_511	Cell_Biology_Alberts	In the simplest case, two identical folded polypeptide chains bind to each other in a “head-to-head” arrangement, forming a symmetric complex of two protein subunits (a dimer) held together by interactions between two identical binding sites. The Cro repressor protein—a viral gene regulatory protein that binds to DNA to turn specific viral genes off in an infected bacterial cell—provides an example (Figure 3–18). Cells contain many other types of symmetric protein complexes, formed from multiple copies of a single polypeptide chain (for example, see Figure 3–20 below). Many of the proteins in cells contain two or more types of polypeptide chains. Hemoglobin, the protein that carries oxygen in red blood cells, contains two identical α-globin subunits and two identical β-globin subunits, symmetrically arranged (Figure 3–19). Such multisubunit proteins are very common in cells, and they can be very large (Movie 3.6).	Cell_Biology_Alberts. In the simplest case, two identical folded polypeptide chains bind to each other in a “head-to-head” arrangement, forming a symmetric complex of two protein subunits (a dimer) held together by interactions between two identical binding sites. The Cro repressor protein—a viral gene regulatory protein that binds to DNA to turn specific viral genes off in an infected bacterial cell—provides an example (Figure 3–18). Cells contain many other types of symmetric protein complexes, formed from multiple copies of a single polypeptide chain (for example, see Figure 3–20 below). Many of the proteins in cells contain two or more types of polypeptide chains. Hemoglobin, the protein that carries oxygen in red blood cells, contains two identical α-globin subunits and two identical β-globin subunits, symmetrically arranged (Figure 3–19). Such multisubunit proteins are very common in cells, and they can be very large (Movie 3.6).
Cell_Biology_Alberts_512	Cell_Biology_Alberts	Most of the proteins that we have discussed so far are globular proteins, in which the polypeptide chain folds up into a compact shape like a ball with an irregular surface. Some of these protein molecules can nevertheless assemble to form filaments that may span the entire length of a cell. Most simply, a long chain of identical protein molecules can be constructed if each molecule has a binding Figure 3–18 Two identical protein subunits binding together to form a symmetric protein dimer. The Cro repressor protein from bacteriophage lambda binds to DNA to turn off a specific subset of viral genes. Its two identical subunits bind head-to-head, held together by a combination of hydrophobic forces (blue) and a set of hydrogen bonds (yellow region). (Adapted from D.H. Ohlendorf, D.E. Tronrud and B.W. Matthews, J. Mol. Biol. 280:129–136, 1998. With permission from Academic Press.)	Cell_Biology_Alberts. Most of the proteins that we have discussed so far are globular proteins, in which the polypeptide chain folds up into a compact shape like a ball with an irregular surface. Some of these protein molecules can nevertheless assemble to form filaments that may span the entire length of a cell. Most simply, a long chain of identical protein molecules can be constructed if each molecule has a binding Figure 3–18 Two identical protein subunits binding together to form a symmetric protein dimer. The Cro repressor protein from bacteriophage lambda binds to DNA to turn off a specific subset of viral genes. Its two identical subunits bind head-to-head, held together by a combination of hydrophobic forces (blue) and a set of hydrogen bonds (yellow region). (Adapted from D.H. Ohlendorf, D.E. Tronrud and B.W. Matthews, J. Mol. Biol. 280:129–136, 1998. With permission from Academic Press.)
Cell_Biology_Alberts_513	Cell_Biology_Alberts	D.E. Tronrud and B.W. Matthews, J. Mol. Biol. 280:129–136, 1998. With permission from Academic Press.) Figure 3–19 a protein formed as a symmetric assembly using two each of two different subunits. Hemoglobin is an abundant protein in red blood cells that contains two copies of α-globin (green) and two copies of β-globin (blue). Each of these four polypeptide chains contains a heme molecule (red), which is the site that binds oxygen (O2). Thus, each molecule of hemoglobin in the blood carries four molecules of oxygen. (PDB code: 2DHB.) Figure 3–20 Protein assemblies. (A) A protein with just one binding site can (A) form a dimer with another identical protein. (B) Identical proteins with two free assembled different binding sites often form a long helical filament. (C) If the two binding subunits structures sites are disposed appropriately in relation to each other, the protein subunits may form a closed ring instead of a helix. (For an example of A, see	Cell_Biology_Alberts. D.E. Tronrud and B.W. Matthews, J. Mol. Biol. 280:129–136, 1998. With permission from Academic Press.) Figure 3–19 a protein formed as a symmetric assembly using two each of two different subunits. Hemoglobin is an abundant protein in red blood cells that contains two copies of α-globin (green) and two copies of β-globin (blue). Each of these four polypeptide chains contains a heme molecule (red), which is the site that binds oxygen (O2). Thus, each molecule of hemoglobin in the blood carries four molecules of oxygen. (PDB code: 2DHB.) Figure 3–20 Protein assemblies. (A) A protein with just one binding site can (A) form a dimer with another identical protein. (B) Identical proteins with two free assembled different binding sites often form a long helical filament. (C) If the two binding subunits structures sites are disposed appropriately in relation to each other, the protein subunits may form a closed ring instead of a helix. (For an example of A, see
Cell_Biology_Alberts_514	Cell_Biology_Alberts	Figure 3–18; for an example of B, see Figure 3–21; for examples of C, see Figures 5–14 and 14–31.) site site complementary to another region of the surface of the same molecule (Figure 3–20). An actin filament, for example, is a long helical structure produced from many molecules of the protein actin (Figure 3–21). Actin is a globular protein that is very abundant in eukaryotic cells, where it forms one of the major filament systems of the cytoskeleton (discussed in Chapter 16).	Cell_Biology_Alberts. Figure 3–18; for an example of B, see Figure 3–21; for examples of C, see Figures 5–14 and 14–31.) site site complementary to another region of the surface of the same molecule (Figure 3–20). An actin filament, for example, is a long helical structure produced from many molecules of the protein actin (Figure 3–21). Actin is a globular protein that is very abundant in eukaryotic cells, where it forms one of the major filament systems of the cytoskeleton (discussed in Chapter 16).
Cell_Biology_Alberts_515	Cell_Biology_Alberts	We will encounter many helical structures in this book. Why is a helix such a common structure in biology? As we have seen, biological structures are often formed by linking similar subunits into long, repetitive chains. If all the subunits are identical, the neighboring subunits in the chain can often fit together in only one way, adjusting their relative positions to minimize the free energy of the contact between them. As a result, each subunit is positioned in exactly the same way in relation to the next, so that subunit 3 fits onto subunit 2 in the same way that subunit 2 fits onto subunit 1, and so on. Because it is very rare for subunits to join up in a straight line, this arrangement generally results in a helix—a regular structure that resembles a spiral staircase, as illustrated in Figure 3–22. Depending on the twist of the staircase, a helix is said to be either right-handed or left-handed (see Figure 3–22E). Handedness is not affected by turning the helix upside down, but	Cell_Biology_Alberts. We will encounter many helical structures in this book. Why is a helix such a common structure in biology? As we have seen, biological structures are often formed by linking similar subunits into long, repetitive chains. If all the subunits are identical, the neighboring subunits in the chain can often fit together in only one way, adjusting their relative positions to minimize the free energy of the contact between them. As a result, each subunit is positioned in exactly the same way in relation to the next, so that subunit 3 fits onto subunit 2 in the same way that subunit 2 fits onto subunit 1, and so on. Because it is very rare for subunits to join up in a straight line, this arrangement generally results in a helix—a regular structure that resembles a spiral staircase, as illustrated in Figure 3–22. Depending on the twist of the staircase, a helix is said to be either right-handed or left-handed (see Figure 3–22E). Handedness is not affected by turning the helix upside down, but
Cell_Biology_Alberts_516	Cell_Biology_Alberts	in Figure 3–22. Depending on the twist of the staircase, a helix is said to be either right-handed or left-handed (see Figure 3–22E). Handedness is not affected by turning the helix upside down, but it is reversed if the helix is reflected in the mirror.	Cell_Biology_Alberts. in Figure 3–22. Depending on the twist of the staircase, a helix is said to be either right-handed or left-handed (see Figure 3–22E). Handedness is not affected by turning the helix upside down, but it is reversed if the helix is reflected in the mirror.
Cell_Biology_Alberts_517	Cell_Biology_Alberts	The observation that helices occur commonly in biological structures holds true whether the subunits are small molecules linked together by covalent bonds (for example, the amino acids in an α helix) or large protein molecules that are linked by noncovalent forces (for example, the actin molecules in actin filaments). This is not surprising. A helix is an unexceptional structure, and it is generated simply by placing many similar subunits next to each other, each in the same strictly repeated relationship to the one before—that is, with a fixed rotation followed by a fixed translation along the helix axis, as in a spiral staircase. Many Protein Molecules Have Elongated, Fibrous Shapes	Cell_Biology_Alberts. The observation that helices occur commonly in biological structures holds true whether the subunits are small molecules linked together by covalent bonds (for example, the amino acids in an α helix) or large protein molecules that are linked by noncovalent forces (for example, the actin molecules in actin filaments). This is not surprising. A helix is an unexceptional structure, and it is generated simply by placing many similar subunits next to each other, each in the same strictly repeated relationship to the one before—that is, with a fixed rotation followed by a fixed translation along the helix axis, as in a spiral staircase. Many Protein Molecules Have Elongated, Fibrous Shapes
Cell_Biology_Alberts_518	Cell_Biology_Alberts	Many Protein Molecules Have Elongated, Fibrous Shapes Enzymes tend to be globular proteins: even though many are large and complicated, with multiple subunits, most have an overall rounded shape. In Figure 3–21, we saw that a globular protein can also associate to form long filaments. But there are also functions that require each individual protein molecule to span a large distance. These proteins generally have a relatively simple, elongated three-dimensional structure and are commonly referred to as fibrous proteins.	Cell_Biology_Alberts. Many Protein Molecules Have Elongated, Fibrous Shapes Enzymes tend to be globular proteins: even though many are large and complicated, with multiple subunits, most have an overall rounded shape. In Figure 3–21, we saw that a globular protein can also associate to form long filaments. But there are also functions that require each individual protein molecule to span a large distance. These proteins generally have a relatively simple, elongated three-dimensional structure and are commonly referred to as fibrous proteins.
Cell_Biology_Alberts_519	Cell_Biology_Alberts	One large family of intracellular fibrous proteins consists of α-keratin, introduced when we presented the α helix, and its relatives. Keratin filaments are extremely stable and are the main component in long-lived structures such as hair, horn, and nails. An α-keratin molecule is a dimer of two identical subunits, with the long α helices of each subunit forming a coiled-coil (see Figure 3–9). The coiled-coil regions are capped at each end by globular domains containing binding sites. This enables this class of protein to assemble into ropelike intermediate filaments—an important component of the cytoskeleton that creates the cell’s internal structural framework (see Figure 16–67).	Cell_Biology_Alberts. One large family of intracellular fibrous proteins consists of α-keratin, introduced when we presented the α helix, and its relatives. Keratin filaments are extremely stable and are the main component in long-lived structures such as hair, horn, and nails. An α-keratin molecule is a dimer of two identical subunits, with the long α helices of each subunit forming a coiled-coil (see Figure 3–9). The coiled-coil regions are capped at each end by globular domains containing binding sites. This enables this class of protein to assemble into ropelike intermediate filaments—an important component of the cytoskeleton that creates the cell’s internal structural framework (see Figure 16–67).
Cell_Biology_Alberts_520	Cell_Biology_Alberts	Fibrous proteins are especially abundant outside the cell, where they are a main component of the gel-like extracellular matrix that helps to bind collections of cells together to form tissues. Cells secrete extracellular matrix proteins into their surroundings, where they often assemble into sheets or long fibrils. Collagen is the most abundant of these proteins in animal tissues. A collagen molecule consists of three long polypeptide chains, each containing the nonpolar amino Figure 3–21 actin filaments. (A) Transmission electron micrographs of negatively stained actin filaments. (B) The helical arrangement of actin molecules in an actin filament. (A, courtesy of Roger Craig.) Figure 3–22 Some properties of a helix.	Cell_Biology_Alberts. Fibrous proteins are especially abundant outside the cell, where they are a main component of the gel-like extracellular matrix that helps to bind collections of cells together to form tissues. Cells secrete extracellular matrix proteins into their surroundings, where they often assemble into sheets or long fibrils. Collagen is the most abundant of these proteins in animal tissues. A collagen molecule consists of three long polypeptide chains, each containing the nonpolar amino Figure 3–21 actin filaments. (A) Transmission electron micrographs of negatively stained actin filaments. (B) The helical arrangement of actin molecules in an actin filament. (A, courtesy of Roger Craig.) Figure 3–22 Some properties of a helix.
Cell_Biology_Alberts_521	Cell_Biology_Alberts	(A–D) A helix forms when a series of subunits bind to each other in a regular way. At the bottom, each of these helices is viewed from directly above the helix and seen to have two (A), three (B), and six (C and D) subunits per helical turn. Note that the helix in (D) has a wider path than that in (C), but the same number of subunits per turn. (E) As discussed in the text, a helix can be either right-handed or left-handed. As a reference, it is useful to remember that standard metal screws, which insert when turned clockwise, are right-handed. Note that a helix retains the same handedness when it is turned upside down. (PDB code: 2DHB.) acid glycine at every third position. This regular structure allows the chains to wind around one another to generate a long regular triple helix (Figure 3–23A). Many collagen molecules then bind to one another side-by-side and end-toend to create long overlapping arrays—thereby generating the extremely tough collagen fibrils that give connective	Cell_Biology_Alberts. (A–D) A helix forms when a series of subunits bind to each other in a regular way. At the bottom, each of these helices is viewed from directly above the helix and seen to have two (A), three (B), and six (C and D) subunits per helical turn. Note that the helix in (D) has a wider path than that in (C), but the same number of subunits per turn. (E) As discussed in the text, a helix can be either right-handed or left-handed. As a reference, it is useful to remember that standard metal screws, which insert when turned clockwise, are right-handed. Note that a helix retains the same handedness when it is turned upside down. (PDB code: 2DHB.) acid glycine at every third position. This regular structure allows the chains to wind around one another to generate a long regular triple helix (Figure 3–23A). Many collagen molecules then bind to one another side-by-side and end-toend to create long overlapping arrays—thereby generating the extremely tough collagen fibrils that give connective
Cell_Biology_Alberts_522	Cell_Biology_Alberts	3–23A). Many collagen molecules then bind to one another side-by-side and end-toend to create long overlapping arrays—thereby generating the extremely tough collagen fibrils that give connective tissues their tensile strength, as described in Chapter 19.	Cell_Biology_Alberts. 3–23A). Many collagen molecules then bind to one another side-by-side and end-toend to create long overlapping arrays—thereby generating the extremely tough collagen fibrils that give connective tissues their tensile strength, as described in Chapter 19.
Cell_Biology_Alberts_523	Cell_Biology_Alberts	Proteins Contain a Surprisingly Large Amount of Intrinsically Disordered Polypeptide Chain It has been well known for a long time that, in complete contrast to collagen, another abundant protein in the extracellular matrix, elastin, is formed as a highly disordered polypeptide. This disorder is essential for elastin’s function. Its relatively loose and unstructured polypeptide chains are covalently cross-linked to short section of 50 nm collagen fbril collagen molecule 300 nm × 1.5 nm 1.5 nm Figure 3–23 Collagen and elastin. (A) Collagen is a triple helix formed by three extended protein chains that wrap around one another (bottom). Many rodlike collagen molecules are cross-linked together in the extracellular space to form unextendable collagen fibrils (top) that have the tensile strength of steel. The striping on the collagen fibril is caused by the regular repeating arrangement of the collagen molecules within the fibril.	Cell_Biology_Alberts. Proteins Contain a Surprisingly Large Amount of Intrinsically Disordered Polypeptide Chain It has been well known for a long time that, in complete contrast to collagen, another abundant protein in the extracellular matrix, elastin, is formed as a highly disordered polypeptide. This disorder is essential for elastin’s function. Its relatively loose and unstructured polypeptide chains are covalently cross-linked to short section of 50 nm collagen fbril collagen molecule 300 nm × 1.5 nm 1.5 nm Figure 3–23 Collagen and elastin. (A) Collagen is a triple helix formed by three extended protein chains that wrap around one another (bottom). Many rodlike collagen molecules are cross-linked together in the extracellular space to form unextendable collagen fibrils (top) that have the tensile strength of steel. The striping on the collagen fibril is caused by the regular repeating arrangement of the collagen molecules within the fibril.
Cell_Biology_Alberts_524	Cell_Biology_Alberts	(B) Elastin polypeptide chains are cross-linked together in the extracellular space to form rubberlike, elastic fibers. Each elastin molecule uncoils into a more extended conformation when the fiber is stretched and recoils spontaneously as soon as the stretching force is relaxed. The cross-linking in the extracellular space mentioned creates covalent linkages between lysine side chains, but the chemistry is different for collagen and elastin. produce a rubberlike, elastic meshwork that can be reversibly pulled from one conformation to another, as illustrated in Figure 3–23B. The elastic fibers that result enable skin and other tissues, such as arteries and lungs, to stretch and recoil without tearing.	Cell_Biology_Alberts. (B) Elastin polypeptide chains are cross-linked together in the extracellular space to form rubberlike, elastic fibers. Each elastin molecule uncoils into a more extended conformation when the fiber is stretched and recoils spontaneously as soon as the stretching force is relaxed. The cross-linking in the extracellular space mentioned creates covalent linkages between lysine side chains, but the chemistry is different for collagen and elastin. produce a rubberlike, elastic meshwork that can be reversibly pulled from one conformation to another, as illustrated in Figure 3–23B. The elastic fibers that result enable skin and other tissues, such as arteries and lungs, to stretch and recoil without tearing.
Cell_Biology_Alberts_525	Cell_Biology_Alberts	Intrinsically disordered regions of proteins are frequent in nature, and they have important functions in the interior of cells. As we have already seen, proteins often have loops of polypeptide chain that protrude from the core region of a protein domain to bind other molecules. Some of these loops remain largely unstructured until they bind to a target molecule, adopting a specific folded conformation only when this other molecule is bound. Many proteins were also known to have intrinsically disordered tails at one or the other end of a structured domain (see, for example, the histones in Figure 4–24). But the extent of such disordered structure only became clear when genomes were sequenced. This allowed bioinformatic methods to be used to analyze the amino acid sequences that genes encode, searching for disordered regions based on their unusually low hydrophobicity and relatively high net charge. Combining these results with other data, it is now thought that perhaps a quarter of	Cell_Biology_Alberts. Intrinsically disordered regions of proteins are frequent in nature, and they have important functions in the interior of cells. As we have already seen, proteins often have loops of polypeptide chain that protrude from the core region of a protein domain to bind other molecules. Some of these loops remain largely unstructured until they bind to a target molecule, adopting a specific folded conformation only when this other molecule is bound. Many proteins were also known to have intrinsically disordered tails at one or the other end of a structured domain (see, for example, the histones in Figure 4–24). But the extent of such disordered structure only became clear when genomes were sequenced. This allowed bioinformatic methods to be used to analyze the amino acid sequences that genes encode, searching for disordered regions based on their unusually low hydrophobicity and relatively high net charge. Combining these results with other data, it is now thought that perhaps a quarter of
Cell_Biology_Alberts_526	Cell_Biology_Alberts	searching for disordered regions based on their unusually low hydrophobicity and relatively high net charge. Combining these results with other data, it is now thought that perhaps a quarter of all eukaryotic proteins can adopt structures that are mostly disordered, fluctuating rapidly between many different conformations. Many such intrinsically disordered regions contain repeated sequences of amino acids. What do these disordered regions do?	Cell_Biology_Alberts. searching for disordered regions based on their unusually low hydrophobicity and relatively high net charge. Combining these results with other data, it is now thought that perhaps a quarter of all eukaryotic proteins can adopt structures that are mostly disordered, fluctuating rapidly between many different conformations. Many such intrinsically disordered regions contain repeated sequences of amino acids. What do these disordered regions do?
Cell_Biology_Alberts_527	Cell_Biology_Alberts	Some known functions are illustrated in Figure 3–24. One predominant function is to form specific binding sites for other protein molecules that are of high specificity, but readily altered by protein phosphorylation, protein dephosphorylation, or any of the other covalent modifications that are triggered by cell signaling events (Figure 3–24A and B). We shall see, for example, that the eukaryotic RNA polymerase enzyme that produces mRNAs contains a long, unstructured C-terminal tail that is covalently modified as its RNA synthesis proceeds, thereby attracting specific other proteins to the transcription complex at different times (see Figure 6–22). And this unstructured tail interacts with a different type of low complexity domain when the RNA polymerase is recruited to the specific sites on the DNA where it begins synthesis.	Cell_Biology_Alberts. Some known functions are illustrated in Figure 3–24. One predominant function is to form specific binding sites for other protein molecules that are of high specificity, but readily altered by protein phosphorylation, protein dephosphorylation, or any of the other covalent modifications that are triggered by cell signaling events (Figure 3–24A and B). We shall see, for example, that the eukaryotic RNA polymerase enzyme that produces mRNAs contains a long, unstructured C-terminal tail that is covalently modified as its RNA synthesis proceeds, thereby attracting specific other proteins to the transcription complex at different times (see Figure 6–22). And this unstructured tail interacts with a different type of low complexity domain when the RNA polymerase is recruited to the specific sites on the DNA where it begins synthesis.
Cell_Biology_Alberts_528	Cell_Biology_Alberts	As illustrated in Figure 3–24C, an unstructured region can also serve as a “tether” to hold two protein domains in close proximity to facilitate their interaction. For example, it is this tethering function that allows substrates to move between active sites in large multienzyme complexes (see Figure 3–54). A similar tethering function allows large scaffold proteins with multiple protein-binding sites to concentrate sets of interacting proteins, both increasing reaction rates and confining their reaction to a particular site in a cell (see Figure 3–78).	Cell_Biology_Alberts. As illustrated in Figure 3–24C, an unstructured region can also serve as a “tether” to hold two protein domains in close proximity to facilitate their interaction. For example, it is this tethering function that allows substrates to move between active sites in large multienzyme complexes (see Figure 3–54). A similar tethering function allows large scaffold proteins with multiple protein-binding sites to concentrate sets of interacting proteins, both increasing reaction rates and confining their reaction to a particular site in a cell (see Figure 3–78).
Cell_Biology_Alberts_529	Cell_Biology_Alberts	Like elastin, other proteins have a function that directly requires that they remain largely unstructured. Thus, large numbers of disordered protein chains in close proximity can create micro-regions of gel-like consistency inside the cell that restrict diffusion. For example, the abundant nucleoporins that coat the inner surface of the nuclear pore complex form a random coil meshwork (Figure 3–24) that is critical for selective nuclear transport (see Figure 12–8).	Cell_Biology_Alberts. Like elastin, other proteins have a function that directly requires that they remain largely unstructured. Thus, large numbers of disordered protein chains in close proximity can create micro-regions of gel-like consistency inside the cell that restrict diffusion. For example, the abundant nucleoporins that coat the inner surface of the nuclear pore complex form a random coil meshwork (Figure 3–24) that is critical for selective nuclear transport (see Figure 12–8).
Cell_Biology_Alberts_530	Cell_Biology_Alberts	Figure 3–24 Some important functions for intrinsically disordered protein sequences. (A) Unstructured regions of polypeptide chain often form binding sites for other proteins. Although these binding events are of high specificity, they are often of low affinity due to the free-energy cost of folding the normally unfolded partner (and they are thus readily reversible). (B) Unstructured regions can be easily modified covalently to change their binding preferences, and they are therefore frequently involved in cell signaling processes. In this schematic, multiple sites of protein phosphorylation are indicated. (C) Unstructured regions frequently create “tethers” that hold interacting protein domains in close proximity. (D) A dense network of unstructured proteins can form a diffusion barrier, as the nucleoporins do for the nuclear pore.	Cell_Biology_Alberts. Figure 3–24 Some important functions for intrinsically disordered protein sequences. (A) Unstructured regions of polypeptide chain often form binding sites for other proteins. Although these binding events are of high specificity, they are often of low affinity due to the free-energy cost of folding the normally unfolded partner (and they are thus readily reversible). (B) Unstructured regions can be easily modified covalently to change their binding preferences, and they are therefore frequently involved in cell signaling processes. In this schematic, multiple sites of protein phosphorylation are indicated. (C) Unstructured regions frequently create “tethers” that hold interacting protein domains in close proximity. (D) A dense network of unstructured proteins can form a diffusion barrier, as the nucleoporins do for the nuclear pore.
Cell_Biology_Alberts_531	Cell_Biology_Alberts	Figure 3–25 Disulfide bonds. Covalent disulfide bonds form between adjacent cysteine side chains. These cross-linkages can join either two parts of the same polypeptide chain or two different polypeptide chains. Since the energy required to break one covalent bond is much larger than the energy required to break even a whole set of noncovalent bonds (see Table 2–1, p. 45), a disulfide bond can have a major stabilizing effect on a protein (Movie 3.7).	Cell_Biology_Alberts. Figure 3–25 Disulfide bonds. Covalent disulfide bonds form between adjacent cysteine side chains. These cross-linkages can join either two parts of the same polypeptide chain or two different polypeptide chains. Since the energy required to break one covalent bond is much larger than the energy required to break even a whole set of noncovalent bonds (see Table 2–1, p. 45), a disulfide bond can have a major stabilizing effect on a protein (Movie 3.7).
Cell_Biology_Alberts_532	Cell_Biology_Alberts	Many protein molecules are either attached to the outside of a cell’s plasma membrane or secreted as part of the extracellular matrix. All such proteins are directly exposed to extracellular conditions. To help maintain their structures, the polypeptide chains in such proteins are often stabilized by covalent cross-linkages. These linkages can either tie together two amino acids in the same protein, or connect different polypeptide chains in a multisubunit protein. Although many other types exist, the most common cross-linkages in proteins are covalent sulfur– sulfur bonds. These disulfide bonds (also called S–S bonds) form as cells prepare newly synthesized proteins for export. As described in Chapter 12, their formation is catalyzed in the endoplasmic reticulum by an enzyme that links together two pairs of –SH groups of cysteine side chains that are adjacent in the folded protein (Figure 3–25). Disulfide bonds do not change the conformation of a protein but instead act as atomic	Cell_Biology_Alberts. Many protein molecules are either attached to the outside of a cell’s plasma membrane or secreted as part of the extracellular matrix. All such proteins are directly exposed to extracellular conditions. To help maintain their structures, the polypeptide chains in such proteins are often stabilized by covalent cross-linkages. These linkages can either tie together two amino acids in the same protein, or connect different polypeptide chains in a multisubunit protein. Although many other types exist, the most common cross-linkages in proteins are covalent sulfur– sulfur bonds. These disulfide bonds (also called S–S bonds) form as cells prepare newly synthesized proteins for export. As described in Chapter 12, their formation is catalyzed in the endoplasmic reticulum by an enzyme that links together two pairs of –SH groups of cysteine side chains that are adjacent in the folded protein (Figure 3–25). Disulfide bonds do not change the conformation of a protein but instead act as atomic
Cell_Biology_Alberts_533	Cell_Biology_Alberts	together two pairs of –SH groups of cysteine side chains that are adjacent in the folded protein (Figure 3–25). Disulfide bonds do not change the conformation of a protein but instead act as atomic staples to reinforce its most favored conformation. For example, lysozyme—an enzyme in tears that dissolves bacterial cell walls—retains its antibacterial activity for a long time because it is stabilized by such cross-linkages.	Cell_Biology_Alberts. together two pairs of –SH groups of cysteine side chains that are adjacent in the folded protein (Figure 3–25). Disulfide bonds do not change the conformation of a protein but instead act as atomic staples to reinforce its most favored conformation. For example, lysozyme—an enzyme in tears that dissolves bacterial cell walls—retains its antibacterial activity for a long time because it is stabilized by such cross-linkages.
Cell_Biology_Alberts_534	Cell_Biology_Alberts	Disulfide bonds generally fail to form in the cytosol, where a high concentration of reducing agents converts S–S bonds back to cysteine –SH groups. Apparently, proteins do not require this type of reinforcement in the relatively mild environment inside the cell. Protein Molecules Often Serve as Subunits for the Assembly of Large Structures The same principles that enable a protein molecule to associate with itself to form rings or a long filament also operate to generate much larger structures formed from a set of different macromolecules, such as enzyme complexes, ribosomes, viruses, and membranes. These large objects are not made as single, giant, covalently linked molecules. Instead they are formed by the noncovalent assembly of many separately manufactured molecules, which serve as the subunits of the final structure. The use of smaller subunits to build larger structures has several advantages: 1.	Cell_Biology_Alberts. Disulfide bonds generally fail to form in the cytosol, where a high concentration of reducing agents converts S–S bonds back to cysteine –SH groups. Apparently, proteins do not require this type of reinforcement in the relatively mild environment inside the cell. Protein Molecules Often Serve as Subunits for the Assembly of Large Structures The same principles that enable a protein molecule to associate with itself to form rings or a long filament also operate to generate much larger structures formed from a set of different macromolecules, such as enzyme complexes, ribosomes, viruses, and membranes. These large objects are not made as single, giant, covalently linked molecules. Instead they are formed by the noncovalent assembly of many separately manufactured molecules, which serve as the subunits of the final structure. The use of smaller subunits to build larger structures has several advantages: 1.
Cell_Biology_Alberts_535	Cell_Biology_Alberts	The use of smaller subunits to build larger structures has several advantages: 1. A large structure built from one or a few repeating smaller subunits requires only a small amount of genetic information. 2. Both assembly and disassembly can be readily controlled reversible processes, because the subunits associate through multiple bonds of relatively low energy. 3. Errors in the synthesis of the structure can be more easily avoided, since correction mechanisms can operate during the course of assembly to exclude malformed subunits.	Cell_Biology_Alberts. The use of smaller subunits to build larger structures has several advantages: 1. A large structure built from one or a few repeating smaller subunits requires only a small amount of genetic information. 2. Both assembly and disassembly can be readily controlled reversible processes, because the subunits associate through multiple bonds of relatively low energy. 3. Errors in the synthesis of the structure can be more easily avoided, since correction mechanisms can operate during the course of assembly to exclude malformed subunits.
Cell_Biology_Alberts_536	Cell_Biology_Alberts	3. Errors in the synthesis of the structure can be more easily avoided, since correction mechanisms can operate during the course of assembly to exclude malformed subunits. Some protein subunits assemble into flat sheets in which the subunits are arranged in hexagonal patterns. Specialized membrane proteins are sometimes arranged this way in lipid bilayers. With a slight change in the geometry of the individual subunits, a hexagonal sheet can be converted into a tube (Figure 3–26) or, with more changes, into a hollow sphere. Protein tubes and spheres that bind specific RNA and DNA molecules in their interior form the coats of viruses.	Cell_Biology_Alberts. 3. Errors in the synthesis of the structure can be more easily avoided, since correction mechanisms can operate during the course of assembly to exclude malformed subunits. Some protein subunits assemble into flat sheets in which the subunits are arranged in hexagonal patterns. Specialized membrane proteins are sometimes arranged this way in lipid bilayers. With a slight change in the geometry of the individual subunits, a hexagonal sheet can be converted into a tube (Figure 3–26) or, with more changes, into a hollow sphere. Protein tubes and spheres that bind specific RNA and DNA molecules in their interior form the coats of viruses.
Cell_Biology_Alberts_537	Cell_Biology_Alberts	The formation of closed structures, such as rings, tubes, or spheres, provides additional stability because it increases the number of bonds between the protein subunits. Moreover, because such a structure is created by mutually dependent, cooperative interactions between subunits, a relatively small change that affects each subunit individually can cause the structure to assemble or disassemble. These principles are dramatically illustrated in the protein coat or capsid of many simple viruses, which takes the form of a hollow sphere based on an icosahedron (Figure 3–27). Capsids are often made of hundreds of identical protein subunits that enclose and protect the viral nucleic acid (Figure 3–28). The protein in such a capsid must have a particularly adaptable structure: not only must it make several different kinds of contacts to create the sphere, it must also change this arrangement to let the nucleic acid out to initiate viral replication once the virus has entered a cell.	Cell_Biology_Alberts. The formation of closed structures, such as rings, tubes, or spheres, provides additional stability because it increases the number of bonds between the protein subunits. Moreover, because such a structure is created by mutually dependent, cooperative interactions between subunits, a relatively small change that affects each subunit individually can cause the structure to assemble or disassemble. These principles are dramatically illustrated in the protein coat or capsid of many simple viruses, which takes the form of a hollow sphere based on an icosahedron (Figure 3–27). Capsids are often made of hundreds of identical protein subunits that enclose and protect the viral nucleic acid (Figure 3–28). The protein in such a capsid must have a particularly adaptable structure: not only must it make several different kinds of contacts to create the sphere, it must also change this arrangement to let the nucleic acid out to initiate viral replication once the virus has entered a cell.
Cell_Biology_Alberts_538	Cell_Biology_Alberts	Many Structures in Cells Are Capable of Self-Assembly The information for forming many of the complex assemblies of macromolecules in cells must be contained in the subunits themselves, because purified subunits can spontaneously assemble into the final structure under the appropriate conditions. The first large macromolecular aggregate shown to be capable of self-assembly from its component parts was tobacco mosaic virus (TMV ). This virus is a long rod in which a cylinder of protein is arranged around a helical RNA core (Figure 3–29). If the dissociated RNA and protein subunits are mixed together in solution, they recombine to form fully active viral particles. The assembly process is unexpectedly complex and includes the formation of double rings of protein, which serve as intermediates that add to the growing viral coat.	Cell_Biology_Alberts. Many Structures in Cells Are Capable of Self-Assembly The information for forming many of the complex assemblies of macromolecules in cells must be contained in the subunits themselves, because purified subunits can spontaneously assemble into the final structure under the appropriate conditions. The first large macromolecular aggregate shown to be capable of self-assembly from its component parts was tobacco mosaic virus (TMV ). This virus is a long rod in which a cylinder of protein is arranged around a helical RNA core (Figure 3–29). If the dissociated RNA and protein subunits are mixed together in solution, they recombine to form fully active viral particles. The assembly process is unexpectedly complex and includes the formation of double rings of protein, which serve as intermediates that add to the growing viral coat.
Cell_Biology_Alberts_539	Cell_Biology_Alberts	Another complex macromolecular aggregate that can reassemble from its component parts is the bacterial ribosome. This structure is composed of about 55 different protein molecules and 3 different rRNA molecules. Incubating a mixture of the individual components under appropriate conditions in a test tube causes them to spontaneously re-form the original structure. Most importantly, such reconstituted ribosomes are able to catalyze protein synthesis. As might be expected, the reassembly of ribosomes follows a specific pathway: after certain proteins have bound to the RNA, this complex is then recognized by other proteins, and so on, until the structure is complete. It is still not clear how some of the more elaborate self-assembly processes are regulated. Many structures in the cell, for example, seem to have a precisely defined length that is many times greater than that of their component macromolecules. How such length determination is achieved is in many cases a mystery. In	Cell_Biology_Alberts. Another complex macromolecular aggregate that can reassemble from its component parts is the bacterial ribosome. This structure is composed of about 55 different protein molecules and 3 different rRNA molecules. Incubating a mixture of the individual components under appropriate conditions in a test tube causes them to spontaneously re-form the original structure. Most importantly, such reconstituted ribosomes are able to catalyze protein synthesis. As might be expected, the reassembly of ribosomes follows a specific pathway: after certain proteins have bound to the RNA, this complex is then recognized by other proteins, and so on, until the structure is complete. It is still not clear how some of the more elaborate self-assembly processes are regulated. Many structures in the cell, for example, seem to have a precisely defined length that is many times greater than that of their component macromolecules. How such length determination is achieved is in many cases a mystery. In
Cell_Biology_Alberts_540	Cell_Biology_Alberts	Figure 3–26 Single protein subunits form protein assemblies that feature multiple protein–protein contacts. Hexagonally packed globular protein subunits are shown here forming either flat sheets or tubes. Generally, such large structures are not considered to be single “molecules.” Instead, like the actin filament described previously, they are viewed as assemblies formed of many different molecules.	Cell_Biology_Alberts. Figure 3–26 Single protein subunits form protein assemblies that feature multiple protein–protein contacts. Hexagonally packed globular protein subunits are shown here forming either flat sheets or tubes. Generally, such large structures are not considered to be single “molecules.” Instead, like the actin filament described previously, they are viewed as assemblies formed of many different molecules.
Cell_Biology_Alberts_541	Cell_Biology_Alberts	Figure 3–27 The protein capsid of a virus. The structure of the simian virus SV40 capsid has been determined by x-ray crystallography and, as for the capsids of many other viruses, it is known in atomic detail. (Courtesy of Robert Grant, Stephan Crainic, and James M. Hogle.) capsid protein intact virus monomer particle shown as (90 dimers) the simplest case, a long core protein or other macromolecule provides a scaffold that determines the extent of the final assembly. This is the mechanism that determines the length of the TMV particle, where the RNA chain provides the core. Similarly, a core protein interacting with actin is thought to determine the length of the thin filaments in muscle.	Cell_Biology_Alberts. Figure 3–27 The protein capsid of a virus. The structure of the simian virus SV40 capsid has been determined by x-ray crystallography and, as for the capsids of many other viruses, it is known in atomic detail. (Courtesy of Robert Grant, Stephan Crainic, and James M. Hogle.) capsid protein intact virus monomer particle shown as (90 dimers) the simplest case, a long core protein or other macromolecule provides a scaffold that determines the extent of the final assembly. This is the mechanism that determines the length of the TMV particle, where the RNA chain provides the core. Similarly, a core protein interacting with actin is thought to determine the length of the thin filaments in muscle.
Cell_Biology_Alberts_542	Cell_Biology_Alberts	Figure 3–28 The structure of a spherical virus. In viruses, many copies of a single protein subunit often pack together to create a spherical shell (a capsid). This capsid encloses the viral genome, composed of either RNA or DNA (see also Figure 3–27). For geometric reasons, no more than 60 identical subunits can pack together in a precisely symmetric way. If slight irregularities are allowed, however, more subunits can be used to produce a larger capsid that retains icosahedral symmetry. The tomato bushy stunt virus (TBSV) shown here, for example, is a spherical virus about 33 nm in diameter formed from 180 identical copies of a 386-amino-acid capsid protein plus an RNA genome of 4500 nucleotides. To construct such a large capsid, the protein must be able to fit into three somewhat different environments. This requires three slightly different conformations, each of which is differently colored in the virus particle shown here. The postulated pathway of assembly is shown; the precise	Cell_Biology_Alberts. Figure 3–28 The structure of a spherical virus. In viruses, many copies of a single protein subunit often pack together to create a spherical shell (a capsid). This capsid encloses the viral genome, composed of either RNA or DNA (see also Figure 3–27). For geometric reasons, no more than 60 identical subunits can pack together in a precisely symmetric way. If slight irregularities are allowed, however, more subunits can be used to produce a larger capsid that retains icosahedral symmetry. The tomato bushy stunt virus (TBSV) shown here, for example, is a spherical virus about 33 nm in diameter formed from 180 identical copies of a 386-amino-acid capsid protein plus an RNA genome of 4500 nucleotides. To construct such a large capsid, the protein must be able to fit into three somewhat different environments. This requires three slightly different conformations, each of which is differently colored in the virus particle shown here. The postulated pathway of assembly is shown; the precise
Cell_Biology_Alberts_543	Cell_Biology_Alberts	environments. This requires three slightly different conformations, each of which is differently colored in the virus particle shown here. The postulated pathway of assembly is shown; the precise three-dimensional structure has been determined by x-ray diffraction. (Courtesy of Steve Harrison.)	Cell_Biology_Alberts. environments. This requires three slightly different conformations, each of which is differently colored in the virus particle shown here. The postulated pathway of assembly is shown; the precise three-dimensional structure has been determined by x-ray diffraction. (Courtesy of Steve Harrison.)
Cell_Biology_Alberts_544	Cell_Biology_Alberts	Figure 3–29 The structure of tobacco mosaic virus (TMV). (A) An electron micrograph of the viral particle, which consists of a single long RNA molecule enclosed in a cylindrical protein coat composed of identical protein subunits. (B) A model showing part of the structure of TMV. A single-stranded RNA molecule of 6395 nucleotides is packaged in a helical coat constructed from 2130 copies of a coat protein 158 amino acids long. Fully infective viral particles can self-assemble in a test tube from purified RNA and protein molecules. (A, courtesy of Robley Williams; B, courtesy of Richard J. Feldmann.)	Cell_Biology_Alberts. Figure 3–29 The structure of tobacco mosaic virus (TMV). (A) An electron micrograph of the viral particle, which consists of a single long RNA molecule enclosed in a cylindrical protein coat composed of identical protein subunits. (B) A model showing part of the structure of TMV. A single-stranded RNA molecule of 6395 nucleotides is packaged in a helical coat constructed from 2130 copies of a coat protein 158 amino acids long. Fully infective viral particles can self-assemble in a test tube from purified RNA and protein molecules. (A, courtesy of Robley Williams; B, courtesy of Richard J. Feldmann.)
Cell_Biology_Alberts_545	Cell_Biology_Alberts	Figure 3–30 Proteolytic cleavage in insulin assembly. The polypeptide hormone insulin cannot spontaneously re-form efficiently if its disulfide bonds are disrupted. It is synthesized as a larger protein (proinsulin) that is cleaved by a proteolytic enzyme after the protein chain has folded into a specific shape. Excision of part of the proinsulin polypeptide chain removes some of the information needed for the protein to fold spontaneously into its normal conformation. Once insulin has been denatured and its two polypeptide chains have separated, its ability to reassemble is lost. Assembly Factors Often Aid the Formation of Complex Biological Structures	Cell_Biology_Alberts. Figure 3–30 Proteolytic cleavage in insulin assembly. The polypeptide hormone insulin cannot spontaneously re-form efficiently if its disulfide bonds are disrupted. It is synthesized as a larger protein (proinsulin) that is cleaved by a proteolytic enzyme after the protein chain has folded into a specific shape. Excision of part of the proinsulin polypeptide chain removes some of the information needed for the protein to fold spontaneously into its normal conformation. Once insulin has been denatured and its two polypeptide chains have separated, its ability to reassemble is lost. Assembly Factors Often Aid the Formation of Complex Biological Structures
Cell_Biology_Alberts_546	Cell_Biology_Alberts	Assembly Factors Often Aid the Formation of Complex Biological Structures Not all cellular structures held together by noncovalent bonds self-assemble. A cilium, or a myofibril of a muscle cell, for example, cannot form spontaneously from a solution of its component macromolecules. In these cases, part of the assembly information is provided by special enzymes and other proteins that perform the function of templates, serving as assembly factors that guide construction but take no part in the final assembled structure.	Cell_Biology_Alberts. Assembly Factors Often Aid the Formation of Complex Biological Structures Not all cellular structures held together by noncovalent bonds self-assemble. A cilium, or a myofibril of a muscle cell, for example, cannot form spontaneously from a solution of its component macromolecules. In these cases, part of the assembly information is provided by special enzymes and other proteins that perform the function of templates, serving as assembly factors that guide construction but take no part in the final assembled structure.
Cell_Biology_Alberts_547	Cell_Biology_Alberts	Even relatively simple structures may lack some of the ingredients necessary for their own assembly. In the formation of certain bacterial viruses, for example, the head, which is composed of many copies of a single protein subunit, is assembled on a temporary scaffold composed of a second protein that is produced by the virus. Because the second protein is absent from the final viral particle, the head structure cannot spontaneously reassemble once it has been taken apart. Other examples are known in which proteolytic cleavage is an essential and irreversible step in the normal assembly process. This is even the case for some small protein assemblies, including the structural protein collagen and the hormone insulin (Figure 3–30). From these relatively simple examples, it seems certain that the assembly of a structure as complex as a cilium will involve a temporal and spatial ordering that is imparted by numerous other components.	Cell_Biology_Alberts. Even relatively simple structures may lack some of the ingredients necessary for their own assembly. In the formation of certain bacterial viruses, for example, the head, which is composed of many copies of a single protein subunit, is assembled on a temporary scaffold composed of a second protein that is produced by the virus. Because the second protein is absent from the final viral particle, the head structure cannot spontaneously reassemble once it has been taken apart. Other examples are known in which proteolytic cleavage is an essential and irreversible step in the normal assembly process. This is even the case for some small protein assemblies, including the structural protein collagen and the hormone insulin (Figure 3–30). From these relatively simple examples, it seems certain that the assembly of a structure as complex as a cilium will involve a temporal and spatial ordering that is imparted by numerous other components.
Cell_Biology_Alberts_548	Cell_Biology_Alberts	A special class of protein structures, utilized for some normal cell functions, can also contribute to human diseases when not controlled. These are self-propagating, stable β-sheet aggregates called amyloid fibrils. These fibrils are built from a series of identical polypeptide chains that become layered one over the other to create a continuous stack of β sheets, with the β strands oriented perpendicular to the fibril axis to form a cross-beta filament (Figure 3–31). Typically, hundreds of monomers will aggregate to form an unbranched fibrous structure that is several micrometers long and 5 to 15 nm in width. A surprisingly large fraction of proteins have the potential to form such structures, because the short segment of the polypeptide chain that forms the spine of the fibril can have a variety of different sequences and follow one of several different paths (Figure 3–32). However, very few proteins will actually form this structure inside cells.	Cell_Biology_Alberts. A special class of protein structures, utilized for some normal cell functions, can also contribute to human diseases when not controlled. These are self-propagating, stable β-sheet aggregates called amyloid fibrils. These fibrils are built from a series of identical polypeptide chains that become layered one over the other to create a continuous stack of β sheets, with the β strands oriented perpendicular to the fibril axis to form a cross-beta filament (Figure 3–31). Typically, hundreds of monomers will aggregate to form an unbranched fibrous structure that is several micrometers long and 5 to 15 nm in width. A surprisingly large fraction of proteins have the potential to form such structures, because the short segment of the polypeptide chain that forms the spine of the fibril can have a variety of different sequences and follow one of several different paths (Figure 3–32). However, very few proteins will actually form this structure inside cells.
Cell_Biology_Alberts_549	Cell_Biology_Alberts	In normal humans, the quality control mechanisms governing proteins gradually decline with age, occasionally permitting normal proteins to form pathological aggregates. The protein aggregates may be released from dead cells and accumulate as amyloid in the extracellular matrix. In extreme cases, the accumulation of such amyloid fibrils in the cell interior can kill the cells and damage tissues. Because the brain is composed of a highly organized collection of nerve cells that cannot regenerate, the brain is especially vulnerable to this sort of cumulative damage. Thus, although amyloid fibrils may form in different tissues, and are known to cause pathologies in several sites in the body, the most severe amyloid pathologies are neurodegenerative diseases. For example, the abnormal formation of highly stable amyloid fibrils is thought to play a central causative role in both Alzheimer’s and Parkinson’s diseases.	Cell_Biology_Alberts. In normal humans, the quality control mechanisms governing proteins gradually decline with age, occasionally permitting normal proteins to form pathological aggregates. The protein aggregates may be released from dead cells and accumulate as amyloid in the extracellular matrix. In extreme cases, the accumulation of such amyloid fibrils in the cell interior can kill the cells and damage tissues. Because the brain is composed of a highly organized collection of nerve cells that cannot regenerate, the brain is especially vulnerable to this sort of cumulative damage. Thus, although amyloid fibrils may form in different tissues, and are known to cause pathologies in several sites in the body, the most severe amyloid pathologies are neurodegenerative diseases. For example, the abnormal formation of highly stable amyloid fibrils is thought to play a central causative role in both Alzheimer’s and Parkinson’s diseases.