Lac repressor Totally Explained

Everything about Lac Repressor totally explained

] The lac repressor is a DNA-binding protein which inhibits the expression of genes coding for proteins involved in the metabolism of lactose in bacteria. It is active in the absence of lactose, ensuring that the bacterium only invests energy in the production of machinery necessary for the uptake and metabolism of lactose when lactose is present. When lactose becomes available, it's converted into allolactose, which inhibits the lac repressor's DNA binding ability.

Function

The lac repressor (LacI) operates by binding to the major groove of the operator region of the lac operon. This blocks RNA polymerase from binding, and so prevents transcription of the mRNA coding for the Lac proteins. When lactose is present, allolactose binds to the lac repressor, causing an allosteric change in its shape. In its changed state, the lac repressor is unable to bind to its cognate operator.
An astute observer might wonder how allolactose could bind LacI if the genes necessary for the conversion of lactose to allolactose are under the control of the lac promoter. It turns out that the number of LacI molecules in a bacterium is low enough that at any given time, some percentage of the cells won't have enough to inhibit transcription. This is an example of biological noise. Given time, more cells in a culture will transiently have no LacI inhibition and will express the lac operon, temporarily conferring the ability to take up lactose and convert it into allolactose. This allolactose binds LacI, increasing the probability of more transcripts being made. This positive feedback loop allows for a small signal (cytoplasmic allolactose concentration) to be amplified and induce a significant change in the cell's gene expression profile. This induced state is epigenetic and somewhat heritable: in cell division, each daughter cell will likely have enough inducer to bind and deactivate LacI.

Structure

The lac repressor protein has three distinct regions:

a core region (which binds allolactose)
a tetramerization region (which joins four monomers in an alpha-helix bundle)
a DNA-binding region (in which two LacI proteins bind a single operator site)

The lac repressor occurs as a tetramer (four identical subunits bound together). This can be viewed as two dimers, with each dimer being able to bind to a single lac operator. The two subunits each bind to a slightly separated (major groove) region of the operator. The promoter is slightly covered by the lac repressor so RNAP can't bind to and transcribe the operon.
The DNA binding region consists of a helix-turn-helix structural motif.

Discovery

The lac repressor was first isolated by Walter Gilbert and Beno Müller-Hill in 1966. They were able to show, in vitro, that the protein bound to DNA containing the lac operon, and released the DNA when IPTG was added. (IPTG is an allolactose analog.) They were also able to isolate the portion of DNA bound by the protein by using the enzyme deoxyribonuclease, which breaks down DNA. After treatment of the repressor-DNA complex, some DNA remained, suggesting that it had been masked by the repressor. This was later confirmed.
These experiments were important, as they confirmed the mechanism of the lac operon, earlier proposed by Jacques Monod and Francois Jacob.

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