If you look closely at the structure shown above, you can see how parts of the protein lie in the grove of double-stranded DNA where they can detect the sequence by "reading" the chemical groups on the edges of the base pairs. It's important to realize that DNA binding proteins interact with the DNA double helix and not with unwound DNA where the individual bases are exposed.
How does a DNA binding protein like lac repressor find its specific site in the genome? The most obvious explanation is that the protein binds non-specifically to any piece of DNA and checks to see if it's a specific binding site. If it is, the protein binds very tightly and doesn't fall off. If it isn't, the interaction is much weaker and the protein falls off quickly so it can check out another potential site.
It's been known for a long time that all specific binding proteins also bind non-specifically. This method of searching for the target site depends on the number of proteins, the size of the genome, and the on-off rates for specific and non-specific binding. The overall rate is limited by diffusion or the rate of collisions between the DNA binding protein and the DNA.
It's also been known for a long time that when the search for the target site is measured in a test tube with purified repressor and purified DNA, the rate of finding the target is FASTER than simple diffusion would predict! What actually happens is that the
Just because this sliding works in vitro, in a test tube, doesn't mean that it works that way in vivo, inside a living cell. The DNA in a cell is covered with lots of other proteins that could block sliding and the concentrations of salts (ionic strength) in the cell are different than the concentrations used in the test tube.
Hammar et al. induced the lac genes and then allowed the lac repressor to re-bind to its target site. They measured the appearance of "fixed" flourescent spots as a function of time. The "fixed" spots represent specific binding to the target sequence.
The rate is faster than a diffusion limited reaction. The data can be fitted to a curve that predicts facilitead diffusion with each search covering about 45 bp of DNA. There were several control experiments and additional experiments showing that the presence of other cellular proteins on the DNA didn't have much of an effect.
The amount of slip slidin' measured in this experiment is close to the value determined in the test tube so it looks like sliding is used inside the cell as well as in vitro. I think we can safely conclude that most specific DNA binding proteins find their target sites by binding non-specifically to DNA then sliding along the double-stranded helix until they find their specific binding site.
1. The two sites are inverted relative to each other so that each subunit is, in theory, binding to exactly the same piece of double-stranded DNA. In practice, the binding sites (operators) differ slightly in their sequences. Furthermore the active repressor inside the cell is actually a tetramer that binds a different piece of DNA are either end (see Repression of the lac Operon).
Hammar, P., Leroy, P., Mahmutovic, A., Marklund, E.G., Berg, O.G., and Elf, J. (2012) The lac repressor displays facilitated diffusion in living cells. Science 336:1595-8. [DOI: 10.1126/science.1221648]
Musical reference: Paul Simon & Art Garfunkel - Slip Slidin' Away