Two styles of transcriptional control of the lac operon

The lac operon is under both negative and positive control. The main contribution of Jacob and Monod was to provide a mechanistic explanation of how a gene could be regulated both negatively and positively; this explanation is called the "operon model".

At the 5' end of the lac operon is a promoter. The promoter is the site where RNA polymerase binds to DNA to initiate transcription. The amount of mRNA produced from a given operon depends on the efficiency of promoter recognition. The lac operon regulates expression of the three lac genes by regulating the efficiency of that process.

Negative Control of Transcription:

Immediately upstream of the three lac genes is a fourth gene which is responsible for negative regulation of the operon. This gene expresses a protein called the lac repressor. The repressor can bind to a short sequence of the lac promoter. When repressor binds to that sequence it physically blocks access by RNA polymerase to the DNA. As a result, as long as it is bound no lac mRNA can be initiated.

The site at which the repressor binds is called an "operator".

When lactose is present in the cell it binds to the repressor protein, inducing a change in its shape. Repressor then can not bind to the operator, and RNA polymerase is no longer prevented from binding to the promoter. As a result, lac mRNA is synthesized. One of the effects of that synthesis is that expression of permease increases drastically. This causes even more lactose to enter the cell, ensuring that the operon will remain fully active until the lactose is no longer present.

Positive Control of Transcription:

Cells would prefer to use glucose as carbon source, even if alternative sources like lactose are present. Therefore the lac operon is only expressed at a high level when glucose is not present.

There are several carbon sources which are used only when glucose is absent: lactose, galactose, & arabinose are three examples. E. coli has evolved a method to control the expression of all of these operons. It turns out that this mechanism is a positive one, that is, when glucose is absent the transcription of each these genes (subject to the presence of the corresponding sugar substrate) can be turned on.

This requires a specific activator protein called CAP (for "catabolite gene activating protein").

The job of CAP is to facilitate initiation of transcription by RNA polymerase on any of these genes. It also turns out that the lac promoter is not very efficient (its sequence is not recognized well by RNA polymerase). CAP protein can bind near the promoter, and facilitate binding by RNA polymerase. CAP can only bind when a small molecule, cyclic AMP or cAMP, binds to the CAP protein first. This is an effect opposite to that of lactose on the repressor. cAMP changes the shape of CAP, making it bind its site on the DNA better.

Therefore, When the concentration of cAMP is lowered, CAP can not bind the cAMP effectively, and thus can not turn on the lac promoter. When glucose is present the concentration of cAMP is very low, and the CAP-dependent genes tend to be transcribed very poorly.

This is a type of control which is common in E. coli. Since one gene product controls the expression of multiple operons this is called "global control". Global positive control is probably the most common form of gene regulation in eukaryotes. Global negative control also occurs commonly, but specific negative control as seen in the lac operon is very rare.