8 Регуляция экспрессии генов. Система передачи сигнала (1160077), страница 10
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This operon is regulated by two mechanisms. When tryptophan levels are high (1) the repressor (upper left) binds its operator and (2) thetranscription of trp mRNA is attenuated, as described in Fig. 27-23.RepressormRNAAttenuatortrpEtrpDtrpC-Regulatory region-Structural genestrp mRNA(low tryptophan levels)AttenuatedmRNA(high tryptophan levels)IAnthranilatesynthase,component IAnthranilatesynthase,[(Col)2 (CoII)2lChorismateI AnthranilateI synthase,component IIJV-( 5' -Phosphoribosyl )anthranilate isomeraseIndole-3-glycerolphosphate synthase>N-( 5 '-Phosphoribosyl)- - >Enol- 1-o-carboxyanthranilatephenylaminoPRPP PPj1-deoxyribulosephosphate• AnthranilateGlutamine GlutamatePyruvateA well-defined example is the E.
coli tryptophan (trp) operon,which includes five genes for the enzymes required to convert chorismate into tryptophan (Fig. 27-21). The mRNA from the trp operon hasa half-life of only about 3 min, allowing the cell to respond rapidly tochanging needs for this amino acid. The Trp repressor is a homodimer,with each subunit containing 107 amino acid residues (Fig. 27-22).When tryptophan is abundant, it binds to the Trp repressor, causing aconformational change that permits the repressor to bind its operator.The trp operator site overlaps the promoter, and binding of the repressor blocks binding of RNA polymerase.Here, as elsewhere, this simple "on/off" circuit mediated by a repressor is not the entire regulatory story.
This system responds to different tryptophan concentrations by varying the rate of synthesis ofthe biosynthetic enzymes over a 700-fold range. Once repression islifted and transcription begins, the rate of transcription is fine-tunedby a second regulatory process called transcription attenuation.Transcription attenuation describes a process in which transcription is initiated normally but is abruptly halted before the operongenes are transcribed.
The frequency with which transcription is attenuated depends on the available concentration of tryptophan. Thebasis for the mechanism, as worked out by Charles Yanofsky, is thevery close coupling between transcription and translation in bacteria.I Tryptophansynthase,/3 subunitTryptophansynthase,a subunitTryptophan synthase• Indole-3-glycerolphosphateGlyceraldehyde-3phosphateL-TryptophanL-SerineFigure 27-22 Structure of the Trp repressor. Thedimeric protein is shown with the helix-turn-helixDNA-binding motifs in red and bound molecules oftryptophan in blue.Chapter 27 Regulation of Gene Expression977activators Spl and CTF1 may act through additional bridging proteinscalled coactivators. The complexity of these interactions, the number ofproteins involved, and the central role of these regulatory processes inthe life of every eukaryote ensure that this will continue to be an areaof vigorous inquiry.Development Is Controlled by a Cascade ofRegulatory ProteinsThe transitions in morphology and protein composition observed in thedevelopment of a zygote into a multicellular animal or plant with manydistinctly different tissues and cell types involve tightly coordinatedchanges in the expression of the organism's genome.
More genes areexpressed during early development than in any other part of the lifecycle. For example, there are about 18,500 different mRNAs in the seaurchin oocyte, but only about 6,000 different mRNAs in the cells oftypical differentiated tissues. The mRNAs present in the oocyte giverise to a cascade of events that not only regulate the expression ofmany genes but also determine where and when the gene products willappear in the developing organism.Several organisms have emerged as important model systems forthe study of development.
These include yeasts, nematodes, fruit flies,sea urchins, frogs, chickens, and mice. Our discussion will focus on thedevelopment of fruit flies. The emerging picture of the molecularevents that occur in development is particularly well advanced in fruitflies and can be used to illustrate patterns and principles of generalsignificance.The fruit fly, Drosophila melanogaster, has a complex life cyclethat includes complete metamorphosis in its progression from an embryo to an adult (Fig. 27-35).
Among the most important characteris- Figure 27-35 The life cycle of the fruitflyDrosotics of the embryo are its polarity (the anterior and posterior, dorsal phila melanogaster. In complete metamorphosis,and ventral parts of the animal are readily distinguished) and its me- the adult insect is radically different in form fromits immature stages; this process requires extensive"remodeling" during development. By the late embryonic stage, segments have formed from whichthe various structures in the adult fly will develop.Late embryo—segmentedEarly embryo—no segmentsn t s ^g&-~.embryonicdevelopmentlarval stages,separated by moltsthreetar"LarvaDay 0 EggDay 5•tfertilizatioiOocyte ^pupationHeadThorax/Abdomenmetamorphosis1 mm(a)(C)Figure 27-38 Distribution of the fushi tarazu (ftz)gene product in early embryos.
In the normal embryo, the gene product can be detected in sevenbands around the circumference of the embryo, asshown schematically in (a). These bands are seenas dark spots (generated by a radioactive label) ina cross-sectional autoradiograph (b), and give riseto the segments shown here in red in the late embryo (c).Figure 27-39 The effects of mutations in homeoticgenes, (a) Normal Drosophila head, (b) Drosophilahomeotic mutant (Antennapaedia) in which antennae are replaced by legs, (c) Normal Drosophilabody structure, (d) Homeotic mutant (Bithorax) inwhich a segment has developed incorrectly to produce an extra set of wings.homeotic genes. One well-characterized segmentation gene is fushitarazu (ftz), which belongs to the "pair-rule" subclass.
When this geneis lost, the embryo develops seven double-wide segments instead of thenormal 14. The mRNAs and proteins derived from the normal ftz geneaccumulate in a striking pattern of seven stripes that encircle the posterior two-thirds of the embryo (Fig. 27-38). The stripes correspond tothe positions of segments that develop later, and which are eliminatedif ftz function is lost. The expression of pattern-regulating genes suchas ftz (and bed, expressed earlier in development) establishes a kind ofchemical blueprint for the body plan that precedes the actual formation of a body structure.Homeotic Genes Loss of homeotic genes by mutation or deletioncauses the appearance of a normal appendage or body structure at aninappropriate body position.
An important example is theultrabithorax (Ubx) gene. When Ubx function is lost, the first abdominal segment develops incorrectly, having the structure of the third thoracic segment. Other known homeotic mutations cause the formationof an extra set of wings, or two legs at the position in the head wherethe antennae are normally found (Fig.
27-39).The homeotic genes span long regions of DNA. The Ubx gene, forexample, is 77,000 base pairs in length and contains introns that are aslong as 50,000 base pairs. Transcription of this gene takes nearly onehour. The delay this imposes on Ubx gene expression is believed to be atiming mechanism involved in the temporal regulation of subsequentsteps in development.The precise nature of many of the events directed by these proteins, and in many cases the biochemical function of the proteins themselves, are unknown. A likely DNA-binding domain has been identified(c)(d)Chapter 27 Regulation of Gene Expression981in a number of these proteins, however, which suggests that they areregulatory proteins.
This domain contains 60 amino acids and is calledthe homeodomain because it was found first in homeotic genes. TheDNA sequence encoding this domain is called the homeobox. It ishighly conserved and has been identified in proteins from a wide variety of organisms. The DNA-binding segment of the domain is related tothe helix-turn-helix motif.The identification of structural determinants with identifiablemolecular functions is the first step in understanding the molecularevents underlying development.
As more genes and their protein products are discovered, the biochemical side of this vast puzzle will slowlycome together.SummaryThe expression of genes is regulated by a numberof processes that affect the rates at which geneproducts are synthesized and degraded. Much ofthis regulation occurs at the level of the initiationof transcription and is mediated by regulatory proteins that either repress or activate transcriptionfrom specific promoters.
Regulation by repressorsand activators is called negative and positive regulation, respectively.In prokaryotes, genes with interdependentfunctions are often clustered as a single transcriptional unit called an operon. The transcription ofoperon genes is generally blocked by the binding ofa specific repressor protein at a DNA site called anoperator. Dissociation of the repressor from theoperator is mediated by a specific small molecule,called an inducer. These principles were first elucidated in studies of the lactose (lac) operon. The Lacrepressor dissociates from the lac operator whenthe repressor binds to the biological inducer, allolactose.Regulatory proteins are DNA-binding proteinsthat recognize specific sequences in the DNA.
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