H. Lodish - Molecular Cell Biology (5ed, Freeman, 2003) (796244), страница 31
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Whether the extracellular deposits of these filaments or the soluble alternatively folded proteins are toxic tothe cell is unclear.73degree of specificity. For instance, an enzyme must first bindspecifically to its target molecule, which may be a small molecule (e.g., glucose) or a macromolecule, before it can executeits specific task. Likewise, the many different types of hormone receptors on the surface of cells display a high degree ofsensitivity and discrimination for their ligands. And, as wewill examine in Chapter 11, the binding of certain regulatoryproteins to specific sequences in DNA is a major mechanismfor controlling genes. Ligand binding often causes a change inthe shape of a protein.
Ligand-driven conformational changesare integral to the mechanism of action of many proteins andare important in regulating protein activity. After considering the general properties of protein–ligand binding, we takea closer look at how enzymes are designed to function as thecell’s chemists.KEY CONCEPTS OF SECTION 3.2Folding, Modification, and Degradation of ProteinsThe amino acid sequence of a protein dictates its folding into a specific three-dimensional conformation, the native state.■Protein folding in vivo occurs with assistance from molecular chaperones (Hsp70 proteins), which bind to nascent polypeptides emerging from ribosomes and preventtheir misfolding (see Figure 3-11).
Chaperonins, large complexes of Hsp60-like proteins, shelter some partly foldedor misfolded proteins in a barrel-like cavity, providing additional time for proper folding.■Subsequent to their synthesis, most proteins are modified by the addition of various chemical groups to aminoacid residues. These modifications, which alter proteinstructure and function, include acetylation, hydroxylation,glycosylation, and phosphorylation.■The life span of intracellular proteins is largely determined by their susceptibility to proteolytic degradation byvarious pathways.■Viral proteins produced within infected cells, normal cytosolic proteins, and misfolded proteins are marked for destruction by the covalent addition of a polyubiquitin chainand then degraded within proteasomes, large cylindricalcomplexes with multiple proteases in their interiors (seeFigure 3-13).■Some neurodegenerative diseases are caused by aggregates of proteins that are stably folded in an alternativeconformation.■3.3 Enzymes and the Chemical Workof CellsProteins are designed to bind every conceivable molecule—from simple ions and small metabolites (sugars, fatty acids) tolarge complex molecules such as other proteins and nucleicacids.
Indeed, the function of nearly all proteins depends ontheir ability to bind other molecules, or ligands, with a highSpecificity and Affinity of Protein–Ligand BindingDepend on Molecular ComplementarityTwo properties of a protein characterize its interaction withligands. Specificity refers to the ability of a protein to bindone molecule in preference to other molecules. Affinityrefers to the strength of binding. The Kd for a protein–ligand complex, which is the inverse of the equilibrium constant Keq for the binding reaction, is the most commonquantitative measure of affinity (Chapter 2).
The strongerthe interaction between a protein and ligand, the lower thevalue of Kd. Both the specificity and the affinity of a proteinfor a ligand depend on the structure of the ligand-bindingsite, which is designed to fit its partner like a mold. Forhigh-affinity and highly specific interactions to take place,the shape and chemical surface of the binding site must becomplementary to the ligand molecule, a property termedmolecular complementarity.The ability of proteins to distinguish different moleculesis perhaps most highly developed in the blood proteins calledantibodies, which animals produce in response to antigens,such as infectious agents (e.g., a bacterium or a virus), andcertain foreign substances (e.g., proteins or polysaccharidesin pollens). The presence of an antigen causes an organism tomake a large quantity of different antibody proteins, eachof which may bind to a slightly different region, or epitope,of the antigen.
Antibodies act as specific sensors for antigens,forming antibody–antigen complexes that initiate a cascadeof protective reactions in cells of the immune system.All antibodies are Y-shaped molecules formed fromtwo identical heavy chains and two identical light chains(Figure 3-15a). Each arm of an antibody molecule containsa single light chain linked to a heavy chain by a disulfidebond. Near the end of each arm are six highly variable loops,called complementarity-determining regions (CDRs), whichform the antigen-binding sites.
The sequences of the six loopsare highly variable among antibodies, making them specificfor different antigens. The interaction between an antibodyand an epitope in an antigen is complementary in all cases;that is, the surface of the antibody’s antigen-binding sitephysically matches the corresponding epitope like a glove74CHAPTER 3 • Protein Structure and Function▲ FIGURE 3-15 Antibody structure and antibody-antigeninteraction.
(a) Ribbon model of an antibody. Every antibodymolecule consists of two identical heavy chains (red) and twoidentical light chains (blue) covalently linked by disulfide bonds.(b) The hand-in-glove fit between an antibody and an epitope onits antigen—in this case, chicken egg-white lysozyme.
Regions(Figure 3-15b). The intimate contact between these two surfaces, stabilized by numerous noncovalent bonds, is responsible for the exquisite binding specificity exhibited by anantibody.The specificity of antibodies is so precise that they candistinguish between the cells of individual members of aspecies and in some cases can distinguish between proteinsthat differ by only a single amino acid. Because of their specificity and the ease with which they can be produced, antibodies are highly useful reagents in many of the experimentsdiscussed in subsequent chapters.Enzymes Are Highly Efficient and SpecificCatalystsIn contrast with antibodies, which bind and simply presenttheir ligands to other components of the immune system, enzymes promote the chemical alteration of their ligands,called substrates.
Almost every chemical reaction in the cellis catalyzed by a specific enzyme. Like all catalysts, enzymesdo not affect the extent of a reaction, which is determined bythe change in free energy G between reactants and products(Chapter 2). For reactions that are energetically favorable(G), enzymes increase the reaction rate by lowering theactivation energy (Figure 3-16). In the test tube, catalystssuch as charcoal and platinum facilitate reactions but usuallyonly at high temperatures or pressures, at extremes of highwhere the two molecules make contact are shown as surfaces.The antibody contacts the antigen with residues from all itscomplementarity-determining regions (CDRs). In this view, thecomplementarity of the antigen and antibody is especiallyapparent where “fingers” extending from the antigen surface areopposed to “clefts” in the antibody surface.or low pH, or in organic solvents.
As the cell’s protein catalysts, however, enzymes must function effectively in aqueousenvironment at 37C, 1 atmosphere pressure, and pH6.5–7.5.Two striking properties of enzymes enable them to function as catalysts under the mild conditions present in cells:their enormous catalytic power and their high degree ofspecificity. The immense catalytic power of enzymes causesthe rates of enzymatically catalyzed reactions to be 106–1012times that of the corresponding uncatalyzed reactions underotherwise similar conditions. The exquisite specificity ofenzymes—their ability to act selectively on one substrate or asmall number of chemically similar substrates —is exemplified by the enzymes that act on amino acids. As noted inChapter 2, amino acids can exist as two stereoisomers, designated L and D, although only L isomers are normally foundin biological systems.
Not surprisingly, enzyme-catalyzed reactions of L-amino acids take place much more rapidly thando those of D-amino acids, even though both stereoisomersof a given amino acid are the same size and possess the sameR groups (see Figure 2-12).Approximately 3700 different types of enzymes, each ofwhich catalyzes a single chemical reaction or set of closely related reactions, have been classified in the enzyme database.Certain enzymes are found in the majority of cells becausethey catalyze the synthesis of common cellular products (e.g.,proteins, nucleic acids, and phospholipids) or take part in the3.3 • Enzymes and the Chemical Work of CellsTransition state(uncatalyzed)Free energy, G∆GuncatTransition state(catalyzed)∆GcatReactantsProductsProgress of reaction▲ FIGURE 3-16 Effect of a catalyst on the activation energyof a chemical reaction.
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