Abstract
Photoreceptor-specific nuclear receptor (PNR, NR2E3) is a key transcriptional regulator of human photoreceptor differentiation and maintenance. Mutations in the NR2E3-encoding gene cause various retinal degenerations, including Enhanced S-cone syndrome, retinitis pigmentosa, and Goldman-Favre disease. Although physiological ligands have not been identified, it is believed that binding of small molecule agonists, receptor desumoylation, and receptor heterodimerization may switch NR2E3 from a transcriptional repressor to an activator. While these features make NR2E3 a potential therapeutic target for the treatment of retinal diseases, there has been a clear lack of structural information for the receptor. Here, we report the crystal structure of the apo NR2E3 ligand binding domain (LBD) at 2.8 Å resolution. Apo NR2E3 functions as transcriptional repressor in cells and the structure of its LBD is in a dimeric auto-repressed conformation. In this conformation, the putative ligand binding pocket is filled with bulky hydrophobic residues and the activation-function-2 (AF2) helix occupies the canonical cofactor binding site. Mutations designed to disrupt either the AF2/cofactor-binding site interface or the dimer interface compromised the transcriptional repressor activity of this receptor. Together, these results reveal several conserved structural features shared by related orphan nuclear receptors, suggest that most disease-causing mutations affect the receptor’s structural integrity, and allowed us to model a putative active conformation that can accommodate small ligands in its pocket.
Highlights
Nuclear receptors (NRs) constitute a large family of DNAbinding transcription factors that modulate gene expression involved in an extremely broad spectrum of physiology
To determine the domain boundaries of the NR2E3 ligand binding domain (LBD), we designed four LBD expression constructs with variations at the N-terminus, starting at either G159, G170, A180, or D192 of full length NR2E3 (Figure 1)
Based on the poor behavior of these proteins and the weak conservation of the NR2E3 LBD N-terminus, we predicted that the NR2E3 LBD might not have an N-terminal helix 1, which is a characteristic of the related orphan nuclear receptor Testicular Receptor 4 (TR4)
Summary
Nuclear receptors (NRs) constitute a large family of DNAbinding transcription factors that modulate gene expression involved in an extremely broad spectrum of physiology. NR2E3 is an orphan nuclear receptor that is highly expressed in photoreceptor cells [2,3,4] and plays pivotal roles in photoreceptor development, differentiation, and survival [4,5,6,7,8,9,10,11,12,13,14,15,16,17]. The human retina contains ~5% cone and ~95% rod photoreceptor cells. Human cones contain one of three alternative pigments (S-, M-, and L-opsins), each, which respond to short (S), medium (M), and long (L) wavelengths for color and brightlight high-resolution vision. NR2E3 is expressed during photoreceptor cell differentiation, but rather is continuously expressed at high levels in mature retina [13,14], consistent with its proposed additional neuroprotective function
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