9.B.208 The Vitamin D3 Receptor (VDR) Family
The steroid hormone, vitamin D3, regulates gene transcription via at least two receptors and initiates putative rapid response systems at the plasma membrane. The vitamin D receptor (VDR) binds vitamin D3 and a second receptor, importin-4, imports the VDR-vitamin D3 complex into the nucleus via nuclear pores. Morrill et al. 2016 presented evidence that the Homo sapiens VDR homodimer contains two transmembrane (TM) helices ((327)E - D(342)), two TM 'half-helix' ((264)K N(276)), one or more large channels, and 16 cholesterol binding (CRAC/CARC) domains. The importin-4 monomer exhibits 3 pore- lining regions ((226)E - L(251); (768)V - G(783); (876)S - A(891)) and 16 CRAC/CARC domains. The MEMSAT algorithm indicated that VDR and importin-4 may not be restricted to cytoplasm and nucleus. The VDR homodimer TM helix-topology predicts insertion into the plasma membrane, with two 84 residue C-terminal regions being extracellular. Similarly, MEMSAT predicts importin-4 insertion into the plasma membrane with 226 residue extracellular N-terminal regions and 96 residue C-terminal extracellular loops; with the pore-lining regions contributing gated Ca2+ channels. The PoreWalker algorithm indicates that, of the 427 residues in each VDR monomer, 91 line the largest channel, including two vitamin D3 binding sites and residues from both the TM helix and 'half-helix'. Cholesterol-binding domains also extend into the channel within the ligand binding region. Programmed changes in bound cholesterol may regulate both membrane Ca2+ response systems and vitamin D3 uptake as well as receptor internalization by the endomembrane system culminating in uptake of the vitamin D3-VDR-importin-4 complex into the nucleus (Morrill et al. 2016).
References:
The Vitamin D3 Receptor, VDR of 427 aas and 0 - 1 TMS. Possibly can insert into the plasma membrane and form a large channel (see family description) (Morrill et al. 2016). It is a dimer with two transmembrane half helices (264K - N276) and 16 cholesterol binding (CRAC/CARC) domains. May function with importin-4 (TC# 1.I.1.1.3) which may also be able to form a transmembrane channel (Morrill et al. 2016).
VDR of Homo sapiens
The bile acid farnesoid receptor, FXR, of 472 or 486 aas but 0 TMSs. The farnesoid X receptor is an important target for the treatment of disorders of bile acid and fatty acid metabolism in mice with nonalcoholic fatty liver disease combined with cholestasis (Liu et al. 2023). FXR, MRP-1 and SLC7A5 are new targets for the treatment of hepatocellular carcinoma (Zhang et al. 2024). SLC7A11, a key protein involved in ferroptosis, and it has been identified as a potential target for drug development. Through screening efforts, novel inhibitors of SLC7A11 have been designed with the aim of promoting ferroptosis and ultimately eliminating cancer cells. Small molecules 42711 and 27363 have been identified as lead compounds with strong inhibitory activity against SLC7A11. Further optimization resulted in the development of a new inhibitor structure (42711_11) (Zhang et al. 2024). FXR-deficiency induces ferroptosis via modulation of CBP-dependent p53 acetylation to suppress breast cancer growth and metastasis (Huang et al. 2024). FXR was first reported as a tumor promoter that enhanced the proliferation and metastasis of breast cancer cells by regulating CBP-dependent p53 K382 acetylation. FXR may serve as a therapeutic target for the treatment of breast cancer.
Farnesoid receptor of Homo sapiens
Nuclear receptor subfamily 1 group I member 2, or the pregnane X recpetor, of 434 aas and 0 TMSs. It binds and is activated by a variety of endogenous and xenobiotic compounds and is a transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. It is activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones in a species-specific fashion. It is also activated by naturally occurring steroids, such as pregnenolone and progesterone (Lehmann et al. 1998; Geick et al. 2001; Watkins et al. 2003; Li et al. 2009).
Pregnane X recpetor of Homo sapiens
Nuclear receptor subfamily 5 group A member 2 of 541 aas. It functions as a key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver and may also contribute to the regulation of pancreas-specific genes while playing important roles in embryonic development (Wang et al. 2005).
Progesterone receptor, PGR, of 933 aas; it is a transcriptional regulatory protein responding to steroids such as progesterone. It has various isoforms of differing functions; isoform 4 increases the mitochondrial membrane potential and cellular respiration upon stimulation by progesterone (Grimm et al. 2016).
PGR of Homo sapiens
Peroxisome proliferator-activated receptor alpha, PPARa or PPARα, of 468 aas. It is a ligand-activated transcription factor that is a key regulator of lipid metabolism.The expression of it structural gene is influenced by emodin (Cheng et al. 2021).
PPARα of Homo sapiens
Oxysterol receptor, LXR-allpha (LXRα) of 447 aas and 0 - 2 TMSs. The effect of liver X receptor agonist TO901317 on cognitive function in APP/PS1 double transgenic mice with Alzheimer's disease and the underlying mechanism have been determined (Luo et al. 2022).
LXRα of Homo sapiens