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).



This family belongs to the .

 

References:

Geick, A., M. Eichelbaum, and O. Burk. (2001). Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J. Biol. Chem. 276: 14581-14587.

Lehmann, J.M., D.D. McKee, M.A. Watson, T.M. Willson, J.T. Moore, and S.A. Kliewer. (1998). The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102: 1016-1023.

Li, Y., J.S. Ross-Viola, N.F. Shay, D.D. Moore, and M.L. Ricketts. (2009). Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner. J Nutr 139: 898-904.

Morrill, G.A., A.B. Kostellow, and R.K. Gupta. (2016). The role of receptor topology in the vitamin D3 uptake and Ca2+ response systems. Biochem. Biophys. Res. Commun. 477: 834-840.

Watkins, R.E., J.M. Maglich, L.B. Moore, G.B. Wisely, S.M. Noble, P.R. Davis-Searles, M.H. Lambert, S.A. Kliewer, and M.R. Redinbo. (2003). 2.1 A crystal structure of human PXR in complex with the St. John''s wort compound hyperforin. Biochemistry 42: 1430-1438.

Examples:

TC#NameOrganismal TypeExample
9.B.208.1.1

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

 
9.B.208.1.2

The bile acid Farnesoid receptor of 472 aas. 

Farnesoid receptor of Homo sapiens

 
9.B.208.1.3

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