Interplay of symmetry and asymmetry in a nuclear receptor
3D structure of the USP/EcR complex, bound to DNA (in blue) on the 5' end of palindromic response elements.
June 19, 2014
Recently installed in the new Centre for Integrative Biology of the IGBMC, the researchers of Bruno Klaholz’s team got interested in the nuclear receptor of ecdysone, an insect hormone, revealing its structure including the hormone and the DNA binding regions. These results, published on June 19th in the journal Nature Communications, highlight an unexpected asymmetry and provide new insights into the overall functioning of steroid receptors.
The nuclear receptors in question
Nuclear receptors are proteins of the cell nucleus which, after being activated by hormones, bind to DNA sequences called "response elements" to enable the expression of certain genes. They are involved in many vital biological functions and are thus potentially privileged targets for the development of new drugs. The precise mechanisms of the specific recognition of the receptor on its DNA binding site are poorly known and addressing this is the aim of the researchers of Bruno Klaholz’s team. Already in 2012, they managed to determine the 3-dimensional structure of the vitamin D receptor (VDR) bound to DNA, a technical challenge given its very small size that makes it barely visible, even with an electron microscope. While the response elements of this type of receptor were two identical repeated sequences, the researchers got interested this time in another family of receptors, the steroid receptors, the response elements of which correspond to a repeated but inverted DNA sequence, suggesting a different mechanism.
An unexpected structure
Estrogens, androgens, progesterone, glucocorticoids… steroid receptors are involved in many diseases. In this large family, the team focused on the ecdysone receptor (EcR), a protein that controls insect molting. EcR binds to another protein, USP, to form a complex that binds to the response elements. The latter are two very similar DNA sequences which, like a palindrome, can be read in the same manner but in the opposite direction on the complementary strand. As these sequences are symmetrical and separated by only one nucleotide, the researchers expected that EcR and USP also bind symmetrically sitting on the DNA "as a rider on a horse." But the results obtained by cryo electron microscopy with a nanometer (one millionth of a millimeter) precision show a different structure. Surprisingly, the two proteins are positioned at one end of the DNA sequence and not at the center of the recognition site, resulting in an asymmetric structure. This topology is similar to that observed for the vitamin D receptor (VDR), but with an inversion of the position of the domain that contains the binding pocket of the hormone on EcR relative to VDR. In short, this unexpected game of symmetry and asymmetry shows that the DNA sequence is crucial as it controls the communication between different parts of the complex, which has implications on how certain genes are regulated.
These results provide new information on the mechanism of action of steroid nuclear receptors and their interaction with molecules able to modulate their efficiency, thus supporting a long-term development of new therapies targeting these receptors.