The trp Operon Is a Repressible Operon with Three Transcription  Units

KEY CONCEPTS
- The trp operon is negatively controlled by the level of its product, the amino acid tryptophan.
- The amino acid tryptophan activates an inactive repressor encoded by trpR.
- A repressor (or activator) will act on all loci that have a copy of its target operator sequence. 

The lac repressor acts only on the operator of the lacZYA cluster. Some repressors, however, control dispersed structural genes by binding at more than one operator. An example is the trp repressor (a small 25-kD homodimeric protein), which controls three unlinked sets of genes:
- An operator at the cluster of structural genes trpEDCBA controls coordinate synthesis of the enzymes that synthesize tryptophan. This is an example of a repressible operon, one that is controlled by the product of the operon—tryptophan .
- The trpR regulator gene is repressed by its own product, the trp repressor. Thus, the repressor protein acts to reduce its own synthesis: It is autoregulated. (Remember, the lacI regulator gene is unregulated.) Such circuits are quite common in regulatory genes and may be either negative or positive .
- An operator at a third locus controls the aroH gene, which codes for one of the three isoenzymes that catalyzes the initial reaction in the common pathway of aromatic amino acid biosynthesis leading to the synthesis of tryptophan, phenylalanine, and tyrosine.

A related 21-bp operator sequence is present at each of the three loci at which the trp repressor acts. The conservation of sequence is indicated in FIGURE 1 . Each operator contains appreciable (but not identical) dyad symmetry. The features conserved at all three operators include the important points of contact for the trp repressor. This explains how one repressor protein acts on several loci: Each locus has a copy of a specific DNA-binding sequence recognized by the repressor (just as each promoter shares consensus sequences with other promoters).

FIGURE 1. The trp repressor recognizes operators at three loci. Conserved bases are shown in red. The location of the start point and mRNA varies, as indicated by the black arrows. 

FIGURE 2 summarizes the variety of relationships between operators and promoters. A notable feature of the dispersed operators recognized by TrpR is their presence at different locations within the promoter in each locus. In trpR the operator lies between positions −12 and +9, whereas in the trp operon it occupies positions −23 to −3. In another gene system, the aroH locus, it lies farther upstream, between −49 and −29. In other cases, the operator can lie either downstream from the promoter (as in lac) or just upstream of the promoter (as in gal, for which the nature of the repressive effect is not quite clear). The ability of the repressors to act at operators whose positions are different in each target promoter suggests possible differences in the exact mode of repression: The common feature is prevention of RNA polymerase initiating transcription at the promoter.

FIGURE 2. Operators may lie at various positions relative to the promoter. 

The trp operon itself is under negative repressible control. This means that the trpR gene product, the trp repressor, is made as an inactive negative regulator. Repression means that the product of the trp operon, the amino acid tryptophan, is a coregulator for the trp repressor. When the level of the amino acid tryptophan builds up, two molecules bind to the dimeric trp repressor, changing its conformation to the active DNA-binding conformation allowing its binding to the operator. This precludes RNA polymerase binding to the overlapping promoter. Up to three trp repressor dimers can bind to the operator, depending on the tryptophan concentration and the concentration of repressor. The central dimer binds the tightest.