DNA-protein binding

The genetic information embodied in DNA must be decoded at the right time and in the right type of cell. To achieve this, proteins that control such processes have to bind to specific places in the genome. How a protein finds the correct spot to bind to among all the possible sites (3 billion base pairs in the human genome, for example) has been the preoccupation of molecular and structural biologists for decades.
A protein could recognize its binding site in the genome by somehow ‘reading’ the DNA and this is the case from studying structures of protein- DNA complexes. The DNA double helix has two grooves, a major and a minor one, that wind around the central axis of the molecule, and reading is achieved using hydrogen bonds that form between protein side chains and the edges of the DNA nucleotides that are exposed in the major groove. But unlike the genetic code, a simple code for protein recognition of DNA has not emerged despite years of effort.
DNA is a molecule with a three-dimensional shape that is not perfectly uniform. Rohs et al. in Nature (2009 p 1248-53 vol 461 1248-1253) show that one structural feature of DNA, the shape of its minor groove, can be exploited by proteins for specific recognition.
A particular sequence of nucleotides presents a unique array of hydrogen-bond donors and acceptors in the major groove, providing a clear mechanism for reading that sequence,
The width of the minor groove varies depending on which nucleotides are present in a segment of DNA. The width of the minor groove has a physical consequence that goes beyond the merely structural, stemming from the charged groups (phosphates) that are arrayed along the outer edge of the DNA backbone, one per nucleotide . Where the minor groove is narrow, the electric-field lines due to the negatively charged phosphates are focused into the groove, leading to an enhanced negative electrostatic potential in that segment of the double helix.
Rohs and colleagues have looked at the databases of three-dimensional structures of protein-DNA complexes and found many examples of proteins that use amino acids containing positively charged side chains, principally arginines, to read the electrostatic potential of the minor groove. Where the groove width and electrostatic potential are optimal, an arginine side chain of a DNA-binding protein is often seen to sit in the minor SI groove

The shape of the minor groove of DNA can direct the binding of proteins to specific sites.
Negatively charged phosphate groups are arrayed along the outer edge of the D A major and minor grooves that spiral around the axis of the double helix. The width of the minor groove varies depending on the sequence of nucleotides. This variation leads to differences in the distance between phosphates across the groove, which in turn lead to variation in the negative electrostatic potential along the minor groove.
Tullius 2009 DNA binding shapes up Nature vol 461 pp 1225-6

Martin Eastwood
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