B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 52
Текст из файла (страница 52)
They often have preciselyengineered moving parts whose mechanical actions are coupled to chemicalevents. It is this coupling of chemistry and movement that gives proteins theextraordinary capabilities that underlie the dynamic processes in living cells.In this section, we explain how proteins bind to other selected molecules andhow a protein’s activity depends on such binding. We show that the ability to bindto other molecules enables proteins to act as catalysts, signal receptors, switches,motors, or tiny pumps. The examples we discuss in this chapter by no meansexhaust the vast functional repertoire of proteins.
You will encounter the specialized functions of many other proteins elsewhere in this book, based on similarprinciples.All Proteins Bind to Other MoleculesA protein molecule’s physical interaction with other molecules determines itsbiological properties. Thus, antibodies attach to viruses or bacteria to mark themfor destruction, the enzyme hexokinase binds glucose and ATP so as to catalyze areaction between them, actin molecules bind to each other to assemble into actinfilaments, and so on.
Indeed, all proteins stick, or bind, to other molecules. Insome cases, this binding is very tight; in others it is weak and short-lived. But thebinding always shows great specificity, in the sense that each protein molecule canusually bind just one or a few molecules out of the many thousands of differenttypes it encounters.
The substance that is bound by the protein—whether it is anion, a small molecule, or a macromolecule such as another protein—is referred toas a ligand for that protein (from the Latin word ligare, meaning “to bind”).The ability of a protein to bind selectively and with high affinity to a liganddepends on the formation of a set of weak noncovalent bonds—hydrogen bonds,electrostatic attractions, and van der Waals attractions—plus favorable hydrophobic interactions (see Panel 2–3, pp. 94–95). Because each individual bond is weak,effective binding occurs only when many of these bonds form simultaneously.Such binding is possible only if the surface contours of the ligand molecule fit veryclosely to the protein, matching it like a hand in a glove (Figure 3–37).PROTEIN FUNCTION135Figure 3–37 The selective binding of aprotein to another molecule. Many weakbonds are needed to enable a proteinto bind tightly to a second molecule, orligand.
A ligand must therefore fit preciselyinto a protein’s binding site, like a handinto a glove, so that a large number ofnoncovalent bonds form between theprotein and the ligand. (A) Schematic;(B) space-filling model. (PDB code: 1G6N.)noncovalent bondsligandbindingsite(B)(A)proteinThe region of a protein that associates with a ligand, known as the ligand’s binding site, usually consists of a cavity in the protein surface formed by a particulararrangement of amino acids. These amino acids can belong to different portionsm3.36/3.33of the polypeptide chain that MBoC6are broughttogether when the protein folds (Figure3–38).
Separate regions of the protein surface generally provide binding sites fordifferent ligands, allowing the protein’s activity to be regulated, as we shall seelater. And other parts of the protein act as a handle to position the protein in thecell—an example is the SH2 domain discussed previously, which often moves aprotein containing it to particular intracellular sites in response to signals.Although the atoms buried in the interior of the protein have no direct contactwith the ligand, they form the framework that gives the surface its contours andits chemical and mechanical properties.
Even small changes to the amino acids inthe interior of a protein molecule can change its three-dimensional shape enoughto destroy a binding site on the surface.Figure 3–38 The binding site of aprotein. (A) The folding of the polypeptidechain typically creates a crevice or cavity onthe protein surface. This crevice contains aset of amino acid side chains disposed insuch a way that they can form noncovalentbonds only with certain ligands. (B) Aclose-up of an actual binding site, showingthe hydrogen bonds and electrostaticinteractions formed between a protein andits ligand. In this example, a molecule ofcyclic AMP is the bound ligand.The Surface Conformation of a Protein Determines Its ChemistryThe impressive chemical capabilities of proteins often require that the chemicalgroups on their surface interact in ways that enhance the chemical reactivity ofone or more amino acid side chains.
These interactions fall into two main categories.First, the interaction of neighboring parts of the polypeptide chain may restrictthe access of water molecules to that protein’s ligand-binding sites. Because watermolecules readily form hydrogen bonds that can compete with ligands for sitesamino acidside chainsHNOHunfolded proteinFOLDINGCCC(CH2)3NHCargininebinding siteHserineCH2hydrogen bondOHOO+NH2NH25′cyclic AMPPOOONHserine3′NOHNOelectrostaticattraction(A)folded proteinNCO_NNCH2CHHOCH2CacidHHHOthreonineCHH3CCCH2 glutamic(B)HH136Chapter 3: ProteinsHAspOCHisOHNCHCreactive serineHNHOSerOCH2COHNCChydrogen bondrearrangementson the protein surface, a ligand will form tighter hydrogen bonds (and electrostatic interactions) with a protein if water molecules are kept away.
It might behard to imagine a mechanism that would exclude a molecule as small as waterfrom a protein surface without affecting the access of the ligand itself. However,because of the strong tendency of water molecules to form water–water hydrogenbonds, water molecules exist in a large hydrogen-bonded network (see Panel 2–2,MBoC6 m3.38/3.35pp. 92–93). In effect, a protein can keep a ligand-bindingsite dry, increasing thatsite's reactivity, because it is energetically unfavorable for individual water molecules to break away from this network—as they must do to reach into a crevice ona protein’s surface.Second, the clustering of neighboring polar amino acid side chains can altertheir reactivity. If protein folding forces together a number of negatively chargedside chains against their mutual repulsion, for example, the affinity of the site fora positively charged ion is greatly increased.
In addition, when amino acid sidechains interact with one another through hydrogen bonds, normally unreactivegroups (such as the –CH2OH on the serine shown in Figure 3–39) can becomereactive, enabling them to be used to make or break selected covalent bonds.The surface of each protein molecule therefore has a unique chemical reactivity that depends not only on which amino acid side chains are exposed, butalso on their exact orientation relative to one another.
For this reason, two slightlydifferent conformations of the same protein molecule can differ greatly in theirchemistry.Sequence Comparisons Between Protein Family MembersHighlight Crucial Ligand-Binding SitesAs we have described previously, genome sequences allow us to group many ofthe domains in proteins into families that show clear evidence of their evolutionfrom a common ancestor.
The three-dimensional structures of members of thesame domain family are remarkably similar. For example, even when the aminoacid sequence identity falls to 25%, the backbone atoms in a domain can follow acommon protein fold within 0.2 nanometers (2 Å).We can use a method called evolutionary tracing to identify those sites in aprotein domain that are the most crucial to the domain’s function. Those sitesthat bind to other molecules are the most likely to be maintained, unchanged asorganisms evolve.
Thus, in this method, those amino acids that are unchanged, ornearly unchanged, in all of the known protein family members are mapped ontoa model of the three-dimensional structure of one family member. When this isdone, the most invariant positions often form one or more clusters on the proteinsurface, as illustrated in Figure 3–40A for the SH2 domain described previously(see Figure 3–6). These clusters generally correspond to ligand-binding sites.The SH2 domain functions to link two proteins together. It binds the proteincontaining it to a second protein that contains a phosphorylated tyrosine sidechain in a specific amino acid sequence context, as shown in Figure 3–40B. Theamino acids located at the binding site for the phosphorylated polypeptide havebeen the slowest to change during the long evolutionary process that producedCNHOCH2CHFigure 3–39 An unusually reactive aminoacid at the active site of an enzyme.This example is the “catalytic triad” AspHis-Ser found in chymotrypsin, elastase,and other serine proteases (see Figure3–12).
The aspartic acid side chain (Asp)induces the histidine (His) to remove theproton from a particular serine (Ser). Thisactivates the serine and enables it to forma covalent bond with an enzyme substrate,hydrolyzing a peptide bond. The manyconvolutions of the polypeptide chain areomitted here.PROTEIN FUNCTION137polypeptide ligandphosphotyrosine(A)FRONTBACK(B)the large SH2 family of peptide recognition domains. Mutation is a random process; survival is not. Thus, natural selection (random mutation followed by nonrandom survival) produces the sequence conservation by preferentially eliminating organisms whose SH2 domains become altered in a way that inactivates theSH2 binding site, destroying SH2 function.Genome sequencing has revealed huge numbers of proteins whose functionsare unknown.
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
