B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 46
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In general, the structure of the different members of aHOOCHOOCNH 2elastaseNH 2chymotrypsinFigure 3–12 A comparison of theconformations of two serine proteases.The backbone conformations of elastaseand chymotrypsin. Although only thoseamino acids in the polypeptide chainshaded in green are the same in the twoproteins, the two conformations are verysimilar nearly everywhere. The active site ofeach enzyme is circled in red; this is wherethe peptide bonds of the proteins thatserve as substrates are bound and cleavedby hydrolysis. The serine proteases derivetheir name from the amino acid serine,whose side chain is part of the active siteof each enzyme and directly participatesin the cleavage reaction. The two dots onthe right side of the chymotrypsin moleculemark the new ends created when thisenzyme cuts its own backbone.Chapter 3: Proteins120(A)(B)helix 2helix 3helix 1COOHNH2(C)H2NyeastG H R F T K E N V R I L E S W F A K N I E N P Y L D T K G L E N L MK N T S L S R I Q I K NWV S N R R R K E K T IR T A F S S E O L A R L K R E F N E N - - - R Y L T E R R R QQ L S S E L G L N E AQ I K I WF QN K R A K I K K SDrosophilaCOOHFigure 3–13 A comparison of a class of DNA-binding domains, called homeodomains, in a pair of proteins fromtwo organisms separated by more than a billion years of evolution.
(A) A ribbon model of the structure common toboth proteins. (B) A trace of the α-carbon positions. The three-dimensional structures shown were determined by x-raycrystallography for the yeast α2 protein (green) and the Drosophila engrailed protein (red). (C) A comparison of amino acidsequences for the region of the proteins shown in (A) and (B). Black dots mark sites with identical amino acids. Orange dotsindicate the position of a three-amino-acid insert in the α2 protein. (Adapted from C. Wolberger et al., Cell 67:517–528, 1991.With permission from Elsevier.)protein family has been more highly conserved than has the amino acid sequence.In many cases, the amino acid sequences have diverged so far that we cannot becertain of a family relationship between two proteins without determining theirm3.13/3.13proteinthree-dimensional structures.
The yeast α2MBoC6and the Drosophila engrailedprotein, for example, are both gene regulatory proteins in the homeodomain family (discussed in Chapter 7). Because they are identical in only 17 of their 60 aminoacid residues, their relationship became certain only by comparing their three-dimensional structures (Figure 3–13). Many similar examples show that two proteins with more than 25% identity in their amino acid sequences usually share thesame overall structure.The various members of a large protein family often have distinct functions.Some of the amino acid changes that make family members different were nodoubt selected in the course of evolution because they resulted in useful changesin biological activity, giving the individual family members the different functionalproperties they have today.
But many other amino acid changes are effectively“neutral,” having neither a beneficial nor a damaging effect on the basic structureand function of the protein. In addition, since mutation is a random process, theremust also have been many deleterious changes that altered the three-dimensionalstructure of these proteins sufficiently to harm them. Such faulty proteins wouldhave been lost whenever the individual organisms making them were at enoughof a disadvantage to be eliminated by natural selection.Protein families are readily recognized when the genome of any organism issequenced; for example, the determination of the DNA sequence for the entirehuman genome has revealed that we contain about 21,000 protein-coding genes.(Note, however, that as a result of alternative RNA splicing, human cells can produce much more than 21,000 different proteins, as will be explained in Chapter6.) Through sequence comparisons, we can assign the products of at least 40% ofour protein-coding genes to known protein structures, belonging to more than500 different protein families.
Most of the proteins in each family have evolvedto perform somewhat different functions, as for the enzymes elastase and chymotrypsin illustrated previously in Figure 3–12. As explained in Chapter 1 (seeFigure 1–21), these are sometimes called paralogs to distinguish them from themany corresponding proteins in different organisms (orthologs, such as mouseand human elastase).THE SHAPE AND STRUCTURE OF PROTEINS121As described in Chapter 8, because of the powerful techniques of x-ray crystallography and nuclear magnetic resonance (NMR), we now know the three-dimensional shapes, or conformations, of more than 100,000 proteins. By carefullycomparing the conformations of these proteins, structural biologists (that is,experts on the structure of biological molecules) have concluded that there area limited number of ways in which protein domains fold up in nature—maybe asfew as 2000, if we consider all organisms. For most of these so-called protein folds,representative structures have been determined.The present database of known protein sequences contains more than twentymillion entries, and it is growing very rapidly as more and more genomes aresequenced—revealing huge numbers of new genes that encode proteins.
Theencoded polypeptides range widely in size, from 6 amino acids to a gigantic protein of 33,000 amino acids. Protein comparisons are important because relatedstructures often imply related functions. Many years of experimentation can besaved by discovering that a new protein has an amino acid sequence similaritywith a protein of known function. Such sequence relationships, for example, firstindicated that certain genes that cause mammalian cells to become cancerousencode protein kinases (discussed in Chapter 20).Some Protein Domains Are Found in Many Different ProteinsAs previously stated, most proteins are composed of a series of protein domains,in which different regions of the polypeptide chain fold independently to formcompact structures.
Such multidomain proteins are believed to have originatedfrom the accidental joining of the DNA sequences that encode each domain, creating a new gene. In an evolutionary process called domain shuffling, many largeproteins have evolved through the joining of preexisting domains in new combinations (Figure 3–14). Novel binding surfaces have often been created at thejuxtaposition of domains, and many of the functional sites where proteins bind tosmall molecules are found to be located there.A subset of protein domains has been especially mobile during evolution;these seem to have particularly versatile structures and are sometimes referred toas protein modules.
The structure of one, the SH2 domain, was illustrated in Figure3–6. Three other abundant protein domains are illustrated in Figure 3–15.Each of the domains shown has a stable core structure formed from strandsof β sheets, from which less-ordered loops of polypeptide chain protrude.
Theloops are ideally situated to form binding sites for other molecules, as most clearlydemonstrated for the immunoglobulin fold, which forms the basis for antibodymolecules. Such β-sheet-based domains may have achieved their evolutionarysuccess because they provide a convenient framework for the generation of newbinding sites for ligands, requiring only small changes to their protruding loops(see Figure 3–42).1 nmimmunoglobulinmodulefibronectintype 3 modulekringlemoduleEGFH2NCOOHCHYMOTRYPSINH2NCOOHUROKINASEH2NCOOHFACTOR IXH2NCOOHPLASMINOGENH2NCOOHFigure 3–14 Domain shuffling.
Anextensive shuffling of blocks of proteinsequence (protein domains) has occurredduring protein evolution. Those portionsof a protein denoted by the same shapeand color in this diagram are evolutionarilyrelated. Serine proteases like chymotrypsinare formed from two domains (brown). Inthe three other proteases shown, whichMBoC6are highly regulated andmorem3.15/3.14specialized,these two protease domains are connectedto one or more domains that are similar todomains found in epidermal growth factor(EGF; green), to a calcium-binding protein(yellow), or to a “kringle” domain (blue).Chymotrypsin is illustrated in Figure 3–12.Figure 3–15 The three-dimensionalstructures of three commonly usedprotein domains.
In these ribbondiagrams, β-sheet strands are shownas arrows, and the N- and C-termini areindicated by red spheres. Many more such“modules” exist in nature. (Adapted fromM. Baron, D.G. Norman and I.D. Campbell,Trends Biochem. Sci. 16:13–17, 1991, withpermission from Elsevier, and D.J. Leahyet al., Science 258:987–991, 1992, withpermission from AAAS.)122Chapter 3: ProteinsFigure 3–16 An extended structure formed from a series of proteindomains. Four fibronectin type 3 domains (see Figure 3–15) from theextracellular matrix molecule fibronectin are illustrated in (A) ribbon and (B)space-filling models. (Adapted from D.J. Leahy, I. Aukhil and H.P.
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