Each cell in your body shares the same DNA. So, for cells to take on their differing roles, they must be able to turn on and off specific genes with precise control. This is achieved in part by DNA binding proteins, which latch onto the genome at particular locations to regulate gene activity.
Scientists have traditionally thought that DNA binding proteins depend on nucleotide sequences to guide them to the right location. However, many proteins bind to multiple letter combinations, and multiple proteins sometimes recognize the same pattern. In a study published today in Cell Systems, scientists at the Gladstone Institutes discovered that proteins must rely on another clue to know where to bind: the DNA’s three-dimensional shape.
Indeed, DNA’s string of letters is also a physical, three-dimensional structure, twisted into a double helix and tightly packaged. Within its ladder-like structure, a variety of twists, grooves, and gaps can be found between the rungs and sides. Pollard and her team realized these variations create a type of keyhole that select proteins slot into. If the grooves on the protein don’t match those on the genome, the key won’t fit.
“There’s a rich scientific literature on how proteins interact with each other or bind to chemicals, and it’s always through a kind of lock and key mechanism; why would proteins binding to DNA be any different?” says first author Md. Abul Hassan Samee.
To test their theory, the researchers adapted a common machine-learning algorithm typically used to identify the letter sequences proteins bind to, except now they looked for patterns in shape. They discovered that over 80% of proteins bind to a specific shape pattern in the genome.
“It was accepted that a pattern of As, Cs, Ts, and Gs where a protein bound to DNA had a particular shape,” says senior author Katherine Pollard. “But nobody had looked to see whether other binding locations that couldn’t be explained with that pattern of letters might have the same shape. If we can show in a dish that proteins can recognize a DNA location because of its shape, even when it doesn’t contain the established letter sequence, I think it would be game changing.”