Image credit: Arek Socha (CC0)
The DNA contains all the information needed to build an organism. It is made up of two strands that wind around each other like a twisted ladder to form the double helix. The strands consist of sugar and phosphate molecules, which attach to one of for bases. Genes are built from DNA, and contain specific sequences of these bases. Being able to modify DNA by deleting, inserting or changing certain sequences allows researchers to engineer tissues or even organisms for therapeutical and practical applications.
One of these gene editing tools is the so-called transcription activator-like effector protein (or TALE for short). TALE proteins are derived from bacteria and are built from simple repeating units that can be linked to form a string-like structure. They have been found to be unstable proteins. To bind to DNA, TALES need to follow the shape of the double helix, adopting a spiral structure, but how exactly TALE proteins thread their way around the DNA is not clear.
To investigate this, Geiger-Schuller et al. monitored single TALE units using fluorescent microscopy. This way, they could exactly measure the time it takes for single TALE proteins to bind and release DNA. The results showed that some TALE proteins bind DNA quickly, whereas others do this slowly. Using a computer model to analyze the different speeds of binding suggested that the fast binding comes from partly unfolded proteins that quickly associate with DNA, and that the slow binding comes from rigid, folded TALE proteins, which have a harder time wrapping around DNA. This suggest that the unstable nature of TALEs, helps these proteins to bind to DNA and turn on genes.
These findings will help to design future TALE-based gene editing tools and also provide more insight into how large molecules can assemble into complex structures. A next step will be to identify TALE repeats with unstable states and to test TALE gene editing tools that have intentionally placed unstable units.
