DNA binding domain of human liver receptor homologue(hLRH-1 DBD) in Complex with dsDNA
Homo sapiens (human)
The ways to transmit the signal in the biological system are so various, because many signal transmitters, for example, neurotransmitters, hormones and others exist. Hence, many receptors which specifically recognize these transmitters also exist. There are two groups of receptors, membrane receptors and nuclear receptors. Nuclear receptors recognize hydrophobic ligands like hormones and regulate gene expression related to various biological processes. After a nuclear receptor recognizes its ligand in the cytoplasmic region, the receptor translocates into the nucleus, binds to its specific DNA sequence, and regulates the gene expression. Many nuclear receptors form homodimers or heterodimers to bind to the DNA, however, the NR5A family (which includes LRH-1, SF-2, and Ftz-F1) joins a small number of other nuclear receptors which bind to DNA as monomers. In adults, LRH-1 is expressed predominantly in the liver and small intestine, and regulates genes involved in bile acid metabolism and cholesterol transport. Nuclear receptors typically have a conserved domain structure, a DNA binding domain (DBD) and a ligand binding domain (LBD). The receptors belonging to the NR5A family additionally contain a C-terminal extension (CTE) and a Ftz-F1 domain after the core of the DBD.
Solomon et al. reported the crystal structure of human LRH-1 DBD in complex with duplex DNA. The DBD domain of LRH-1 has two Cys4-type Zn module domains which fit in the major groove of the AGGYCR sequence and recognize the six bases. While nuclear receptors which work as dimer recognize only six bases, LRH-1 recognizes an additional three bases with the CTE. The CTE of LRH-1 fits in the minor groove of the YCA sequence which is the 5'-extension beyond the AGGYCR, thus LRH-1 recognizes nine bases (YCAAGGYCR). The Ftz-F1 domain is located after the CTE and folds into an alpha-helix which does not contact the DNA, but is assumed to interact with LBD and transcriptional cofactors. Since the alpha-helix of Ftz-F1 domain packs against the DBD, mutation in the Ftz-F1 sequence is expected to eliminate the DNA binding. Surprisingly, the mutation does not eliminate the DNA binding ability of LRH-1 but reduce the transcriptional efficiency. Nuclear receptor DBDs and LBDs have been thought to operate independently because the linker that connects them is flexible. However, this result indicates that subtle structural change in a nuclear receptor DBD can exert long range functional effects on the LBD of a receptor, and significantly impact transcriptional regulation.
Protein Data Bank (PDB)
author: Daisuke Ino