Lac repressor

From Proteopedia

Revision as of 17:03, 16 October 2008

What is the lac repressor?

Repressors are proteins that inhibit the expression of genes; that is, they inhibit the transcription of messenger RNA from their target genes. Each repressor targets a specific co-regulated group of genes by recognizing a specific sequence of DNA, called the operator in bacteria. Repressor proteins are coded for by regulatory genes.

The lactose ("lac") repressor controls the expression of bacterial enzymes involved in the metabolism of of the sugar lactose. When the lac repressor binds lactose, it changes to an inactive conformation that cannot repress the production of these enzymes. Thus, the enzymes needed to use lactose are made only when lactose is available. The lac repressor, and the group of genes it controls, which is called an operon, were the first such gene regulatory system to be discovered. The operon was described in 1960^[1] by François Jacob et al., who also correctly proposed the general mechanism of regulation by the lac repressor. The 1965 Nobel Prize in Physiology or Medicine was awarded to François Jacob, André Lwoff, and Jacques Monod "for their discoveries concerning genetic control of enzyme and virus synthesis".

For a general introduction to the lac repressor, please see David Goodsell's Introduction to the lac repressor in his series Molecule of the Month, and the article in Wikipedia on the lac repressor. Mitchell Lewis published a detailed review in 2005^[2].

Structure of the lac repressor

The lac repressor protein ( showing chain A in 1lbg, resolution 4.8 Å), starting at the N-terminus, begins with a DNA-binding "headpiece", followed by a hinge region, then an N-terminal ligand-binding subdomain and a C-terminal ligand binding subdomain, a linker, and a C-terminal tetramerization helix^[3]. In the absence of DNA, the hinge region does not form the alpha helix shown here.

As can be seen when the chain is

each of the ligand-binding subdomains is made up of two discontinuous segments.

The lac repressor forms . Dimerization buries 2,200 Ų of surface, including a ,

forming a hydrophobic core (shown with 1lbi, resolution 2.7 Å, lacking the DNA-binding domain due to disorder).

The most highly is the surface that contacts DNA^[4]. (Only alpha carbon atoms are shown here, without sidechains, because sidechains were not resolved in the 4.8 Å 1lbg model.) The dimerization surfaces are the of the ligand-binding domains^[5]. (This scene shows sidechains, using the 2.7 Å model in 1lbi, which lacks the DNA-binding domain due to disorder.)

The C-terminal tetramerization helices tether two dimers, and thus the functional form of with two DNA-binding sites.

DNA Binding: Bending the Operator

Non-Specific Binding

Lac repressor binds to DNA non-specifically (, 20 NMR models), enabling it to slide rapidly along the DNA double helix until it encounters the lac operator sequence. The DNA-binding domain employs a helix-turn-helix motif (Alpha Helices, Turns). During non-specific binding, the hinge region is disordered (indicated by the range of positions of the 20 models), and the DNA double helix is straight. The model shown at right (1osl) has two copies of the DNA-binding domain and hinge region ( to distinguish the chain B hinge). these 20 NMR models simulates thermal motion of the disordered hinge regions.

Specific Binding

Upon recognizing the specific operator sequence, the non-specific binding converts to . During this conversion, the hinge region changes from disordered loops to Alpha Helices (), which binds in the minor groove of the DNA. This binding opens the minor groove, bending the DNA double helix.

Morph of Conversion

The changes during conversion from non-specific to specific binding can be seen more easily when they are by morphing. (The methods used to create this morph are given in Lac repressor morph methods.)

.... forming sequence-specific hydrogen bonds with DNA bases.

To Be Continued .... Eric Martz 23:52, 14 October 2008 (IST)

Content Attribution

The morphs displayed here were originally prepared by Eric Martz in 2004 for the page Lac Repressor Binding to DNA, within ProteinExplorer.Org.

References

1. ↑ L'opéron: groupe de gènes à expression coordonée par un opérateur. [Operon: a group of genes with the expression coordinated by an operator.] C R Hebd Seances Acad Sci., 250:1727-9, 1960. PubMed 14406329
2. ↑ The lac repressor. Lewis, M. C R Biol. 328:521-48, 2005. PubMed 15950160
3. ↑ This domain coloring scheme is adapted from Fig. 6 in the review by Lewis (C. R. Biol. 328:521, 2005). Domains are 1-45, 46-62, (63-162,291-320), (163-290,321-332), 330-339, and 340-357.
4. ↑ Conservation results for 1lbg are from the precalculated ConSurf Database, using 103 sequences from Swiss-Prot with an average pairwise distance of 2.4.
5. ↑ Conservation results for 1lbi are from the ConSurf Server, using 100 sequences from Uniprot with an average pairwise distance of 1.3.