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7-22), the process is envisioned as hierarchical, following the levels of structure outlined at thebeginning of this chapter. Local secondary structures would form first,followed by longer-range interactions between, say, two a helices withcompatible amino acid side chains, a process continuing until foldingChapter 7 The Three-Dimensional Structure of Proteinsj183iuRight-handed(a)Left-handed(b)was complete. In an alternative model, folding is initiated by a spontaneous collapse of the polypeptide into a compact state mediated byhydrophobic interactions among nonpolar residues.
The state resultingfrom this "hydrophobic collapse" may have a high content of secondarystructure, but many amino acid side chains are not entirely fixed. Either or both models (and perhaps others) may apply to a given protein.A number of structural constraints help to guide the interaction ofregions of secondary structure. The most common patterns are sometimes referred to as supersecondary structures. A prominent one is atendency for extended (3 conformations to twist in a right-handed sense(Fig.
7-23a). This influences both the arrangement of /3 sheets relativeto one another and the path of the polypeptide segment connecting twoj8 strands. Two parallel f3 strands, for example, must be connected by acrossover strand (Fig. 7-23b). In principle, this crossover could have aright- or left-handed conformation, but only the right-handed form isfound in proteins. The twisting of /3 sheets also leads to a characteristictwisting of the structure formed when many sheets are put together.Two examples of resulting structures are the /3 barrel and saddleshapes (Fig. 7-23d), which form the core of many larger structures.Weak-bonding interactions represent the ultimate thermodynamicconstraint on the interaction of different regions of secondary structure.
The R groups of amino acids project outward from a-helical and f3structures, and thus the need to bury hydrophobic residues means thatwater-soluble proteins must have more than one layer of secondarystructure. One simple structural method for burying hydrophobic residues is a supersecondary structural unit called a /3a/3 loop (Fig. 7-24),a structure often repeated multiple times in larger proteins. More elaborate structures are domains made up of facing ft sheets (with hydrophobic residues sandwiched between), and f3 sheets covered on one sidewith several a helices, as described later.SaddleP Barrel(d)Figure 7-23 Extended p chains of amino acidstend to twist in a right-handed sense because theslightly twisted conformation is more stable thanthe linear conformation (a).
This influences theconformation of the polypeptide segments that connect two ft strands, and also the stable conformations assumed by several adjacent p strands,(b) Connections between parallel p chains areright-handed, (c) The p turn is a common connector between antiparallel p chains, (d) The tendencyfor right-handed twisting is seen in two particularlystable arrangements of adjacent p chains: theP barrel and the saddle; these structuresform the stable core of many proteins.Figure 7-24 The pap loop.
The shaded regiondenotes the area where stabilizing hydrophobic interactions occur.184Part II Structure and CatalysisIt becomes more difficult to bury hydrophobic residues in smallerstructures, and the number of potential weak interactions available forstabilization decreases. For this reason, smaller proteins are often heldtogether with a number of covalent bonds, principally disulfide linkages. Recall the multiple disulfide bonds in the small proteins insulin(see Fig. 6-10) and ribonuclease (Fig. 7-21).
Other types of covalentbonds also occur. The heme group in cytochrome c, for example, iscovalently linked to the protein on two sides, providing a significantstabilization of the entire protein structure.Not all proteins fold spontaneously as they are synthesized in thecell. Proteins that facilitate the folding of other proteins have beenfound in a wide variety of cells. These are called polypeptide chainbinding proteins or molecular chaperones.
Several of these proteinscan bind to polypeptide chains, preventing nonspecific aggregation ofweak-bonding side chains. They guide the folding of some polypeptides, as well as the assembly of multiple polypeptides into largerstructures. Dissociation of polypeptide chain binding proteins frompolypeptides is often coupled to ATP hydrolysis.
One family of suchproteins has structures that are highly conserved in organisms ranging from bacteria to mammals. These proteins (Mr 70,000), as well asseveral other families of polypeptide chain binding proteins, were originally identified as "heat shock" proteins because they are induced inmany cells when heat stress is applied, and apparently help stabilizeother proteins.Some proteins have also been found that promote polypeptide folding by catalyzing processes that otherwise would limit the rate of folding, such as the reversible formation of disulfide bonds or proline isomerization (the interconversion of the cis and trans isomers of peptidebonds involving the imino nitrogen of proline; see Fig.
7-10).There Are a Few Common Tertiary Structural PatternsFollowing the folding patterns outlined above and others yet to be discovered, a newly synthesized polypeptide chain quickly assumes itsmost stable tertiary structure. Although each protein has a uniquestructure, several patterns of tertiary structure seem to occur repeatedly in proteins that differ greatly in biological function and aminoacid sequence (Fig. 7-25). This may reflect an unusual degree of stability and/or functional flexibility conferred by these particular tertiarystructures. It also demonstrates that biological function is determinednot only by the overall three-dimensional shape of the protein, but alsoby the arrangement of amino acids within that shape.One structural motif is made up of eight j8 strands arranged in acircle with each /3 strand connected to its neighbor by an a helix.
The j8regions are arranged in the barrel structure described in Figure 7-23,and they influence the overall tertiary structure, giving rise to thename a/p barrel (Fig. 7-25a). This structure is found in many enzymes; a binding site for a cofactor or substrate is often found in apocket formed near an end of the barrel.Another structural motif is the four-helix bundle (Fig. 7-25b), inwhich four a helices are connected by three peptide loops.
The helicesare slightly tilted to form a pocket in the middle, which often contains abinding site for a metal or other cofactors essential for biological function. A somewhat similar structure in which seven helices are ar-185Chapter 7 The Three-Dimensional Structure of Proteinsalp BarrelFour-helix bundlewith saddle at corep-p SandwichV>*VPyruvate kinasedomain 1(top view)Cytochrome 6 562CarboxypeptidaseTriose phosphateisomerase(top view)Myohemerythrin(top view)Lactatedehydrogenasedomain 1(c)Triose phosphateisomerase(side view)(a)Myohemerythrin(side view)(b)ranged in a barrel-like motif is found in some membrane proteins (seeFig.
10-10). The seven helices often surround a channel that spans themembrane.A third motif has a (3 sheet in the "saddle" conformation forming astable core, often surrounded by a number of a-helical regions (Fig.7-25c). Structures of this kind are found in many enzymes. The location of the substrate binding site varies, determined by the placementof the a helices and other variable structural elements.One final motif makes use of a sandwich of /3 sheets, layered sothat the strands of the sheets form a quiltlike cross-hatching whenviewed from above (Fig. 7-25d).
This creates a hydrophobic pocketbetween the /3 sheets that is often a binding site for a planar hydrophobic molecule.Insecticyanina r Antitrypsin(d)Figure 7-25 Examples of some common structuralmotifs in proteins, (a) The a//3 barrel, found in pyruvate kinase and triose phosphate isomerase, enzymes of the glycolytic pathway. This structure alsooccurs in the larger domain of ribulose-l,5-bisphosphate carboxylase/oxygenase (known also asrubisco), an enzyme essential to the fixation of CO2by plants; in glycolate oxidase, an enzyme in photorespiration; and in a number of other unrelatedproteins, (b) The four-helix bundle, shown here incytochrome 6562 and myohemerythrin. A dinucleariron center and coordinating amino acids inmyohemerythrin are shown in orange.
Myohemerythrin is a nonheme oxygen-transporting protein found in certain worms and mollusks. Thefour-helix bundle is also found in apoferritin andthe tobacco mosaic virus coat-protein. Apoferritin isa widespread protein involved in iron transport andstorage, (c) ap with saddle at core, in carboxypeptidase, a protein-hydrolyzing (proteolytic) enzyme,and lactate dehydrogenase, a glycolytic enzyme,(d) fi-p Sandwich. In the protein insecticyanin ofmoths, the hydrophobic pocket binds biliverdin, acolored substance that plays a role in camouflage.arAntitrypsin is a naturally occurring inhibitor ofthe proteolytic enzyme trypsin.(a)One heme is bound to each polypeptide chain of hemoglobin. Theoxygen-binding sites are rather far apart given the size of the molecule,about 2.5 nm from one another.
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