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Transmembrane helices in "classical" nuclear reproductive steroid receptors: a perspective.

Morrill GA, Kostellow AB, Gupta RK - Nucl Recept Signal (2015)

Bottom Line: The data suggest that (except for ER2), cytosolic receptors become anchored to the plasma membrane following synthesis.Half-helices and pore-lining regions in turn form functional ion channels and/or facilitate passive steroid uptake into the cell.In perspective, steroid-dependent insertion of "classical" receptors containing pore-lining regions into the plasma membrane may regulate permeability to ions such as Ca(2+), Na(+) or K(+), as well as facilitate steroid translocation into the nucleus.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461 USA.

ABSTRACT
Steroid receptors of the nuclear receptor superfamily are proposed to be either: 1) located in the cytosol and moved to the cell nucleus upon activation, 2) tethered to the inside of the plasma membrane, or 3) retained in the nucleus until free steroid hormone enters and activates specific receptors. Using computational methods to analyze peptide receptor topology, we find that the "classical" nuclear receptors for progesterone (PRB/PGR), androgen (ARB/AR) and estrogen (ER1/ESR1) contain two transmembrane helices (TMH) within their ligand-binding domains (LBD).The MEMSAT-SVM algorithm indicates that ARB and ER2 (but not PRB or ER1) contain a pore-lining (channel-forming) region which may merge with other pore-lining regions to form a membrane channel. ER2 lacks a TMH, but contains a single pore-lining region. The MemBrain algorithm predicts that PRB, ARB and ER1 each contain one TMH plus a half TMH separated by 51 amino acids.ER2 contains two half helices. The TM-2 helices of ARB, ER1 and ER2 each contain 9-13 amino acid motifs reported to translocate the receptor to the plasma membrane, as well as cysteine palmitoylation sites. PoreWalker analysis of X-ray crystallographic data identifies a pore or channel within the LBDs of ARB and ER1 and predicts that 70 and 72 residues are pore-lining residues, respectively. The data suggest that (except for ER2), cytosolic receptors become anchored to the plasma membrane following synthesis. Half-helices and pore-lining regions in turn form functional ion channels and/or facilitate passive steroid uptake into the cell. In perspective, steroid-dependent insertion of "classical" receptors containing pore-lining regions into the plasma membrane may regulate permeability to ions such as Ca(2+), Na(+) or K(+), as well as facilitate steroid translocation into the nucleus.

No MeSH data available.


A schematic 2-D representation of a protein-ligand complex of dihydrotestosterone (DHT) and rat ARB (1i37, P15207) using LIGPLOT [Wallace et al., 1995] and the standard PDB file input.The interactions shown are those mediated by hydrogen bonds and by hydrophobic contacts. Hydrogen bonds are indicated by dashed lines between the atoms involved, while hydrophobic contacts are represented by an arc with spokes radiating towards the ligand atoms they contact. The contacted atoms are shown with spokes radiating back.
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f8: A schematic 2-D representation of a protein-ligand complex of dihydrotestosterone (DHT) and rat ARB (1i37, P15207) using LIGPLOT [Wallace et al., 1995] and the standard PDB file input.The interactions shown are those mediated by hydrogen bonds and by hydrophobic contacts. Hydrogen bonds are indicated by dashed lines between the atoms involved, while hydrophobic contacts are represented by an arc with spokes radiating towards the ligand atoms they contact. The contacted atoms are shown with spokes radiating back.

Mentions: The upper part (A) of Figure 7 illustrates the crystal structure of the ligand binding domain of rat ARB (1i37, P15207). The transmembrane helices (TMH) identified in Figure 1 are indicated both above the center and in the upper right of the graphic in Figure 7 by “TMH” and correspond to residues 738Q – R752 (center TMH) and residues 803E – F813 (upper right) as predicted in Table 4. As noted in Table 4, both putative TM helices contain residues identified as pore-lining amino acids by PoreWalker (Table 4). The lower part (B) of Figure 7 illustrates the secondary structure of the 246 residues of rat ARB 1i37 (P15207). Eleven helical regions are indicated as purple coils and defined as H1, H2 etc. The TM helices predicted in the JMol projection (Figure 8) correspond to H3 – H4 and H5-β-H6 in the “classical” PDB projection in B (lower image). The region between 753S and Q802 corresponds to the putative 51 amino acid extracellular loop (described above) and contains 3 β strand structures (indicated in yellow).


Transmembrane helices in "classical" nuclear reproductive steroid receptors: a perspective.

Morrill GA, Kostellow AB, Gupta RK - Nucl Recept Signal (2015)

A schematic 2-D representation of a protein-ligand complex of dihydrotestosterone (DHT) and rat ARB (1i37, P15207) using LIGPLOT [Wallace et al., 1995] and the standard PDB file input.The interactions shown are those mediated by hydrogen bonds and by hydrophobic contacts. Hydrogen bonds are indicated by dashed lines between the atoms involved, while hydrophobic contacts are represented by an arc with spokes radiating towards the ligand atoms they contact. The contacted atoms are shown with spokes radiating back.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590301&req=5

f8: A schematic 2-D representation of a protein-ligand complex of dihydrotestosterone (DHT) and rat ARB (1i37, P15207) using LIGPLOT [Wallace et al., 1995] and the standard PDB file input.The interactions shown are those mediated by hydrogen bonds and by hydrophobic contacts. Hydrogen bonds are indicated by dashed lines between the atoms involved, while hydrophobic contacts are represented by an arc with spokes radiating towards the ligand atoms they contact. The contacted atoms are shown with spokes radiating back.
Mentions: The upper part (A) of Figure 7 illustrates the crystal structure of the ligand binding domain of rat ARB (1i37, P15207). The transmembrane helices (TMH) identified in Figure 1 are indicated both above the center and in the upper right of the graphic in Figure 7 by “TMH” and correspond to residues 738Q – R752 (center TMH) and residues 803E – F813 (upper right) as predicted in Table 4. As noted in Table 4, both putative TM helices contain residues identified as pore-lining amino acids by PoreWalker (Table 4). The lower part (B) of Figure 7 illustrates the secondary structure of the 246 residues of rat ARB 1i37 (P15207). Eleven helical regions are indicated as purple coils and defined as H1, H2 etc. The TM helices predicted in the JMol projection (Figure 8) correspond to H3 – H4 and H5-β-H6 in the “classical” PDB projection in B (lower image). The region between 753S and Q802 corresponds to the putative 51 amino acid extracellular loop (described above) and contains 3 β strand structures (indicated in yellow).

Bottom Line: The data suggest that (except for ER2), cytosolic receptors become anchored to the plasma membrane following synthesis.Half-helices and pore-lining regions in turn form functional ion channels and/or facilitate passive steroid uptake into the cell.In perspective, steroid-dependent insertion of "classical" receptors containing pore-lining regions into the plasma membrane may regulate permeability to ions such as Ca(2+), Na(+) or K(+), as well as facilitate steroid translocation into the nucleus.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461 USA.

ABSTRACT
Steroid receptors of the nuclear receptor superfamily are proposed to be either: 1) located in the cytosol and moved to the cell nucleus upon activation, 2) tethered to the inside of the plasma membrane, or 3) retained in the nucleus until free steroid hormone enters and activates specific receptors. Using computational methods to analyze peptide receptor topology, we find that the "classical" nuclear receptors for progesterone (PRB/PGR), androgen (ARB/AR) and estrogen (ER1/ESR1) contain two transmembrane helices (TMH) within their ligand-binding domains (LBD).The MEMSAT-SVM algorithm indicates that ARB and ER2 (but not PRB or ER1) contain a pore-lining (channel-forming) region which may merge with other pore-lining regions to form a membrane channel. ER2 lacks a TMH, but contains a single pore-lining region. The MemBrain algorithm predicts that PRB, ARB and ER1 each contain one TMH plus a half TMH separated by 51 amino acids.ER2 contains two half helices. The TM-2 helices of ARB, ER1 and ER2 each contain 9-13 amino acid motifs reported to translocate the receptor to the plasma membrane, as well as cysteine palmitoylation sites. PoreWalker analysis of X-ray crystallographic data identifies a pore or channel within the LBDs of ARB and ER1 and predicts that 70 and 72 residues are pore-lining residues, respectively. The data suggest that (except for ER2), cytosolic receptors become anchored to the plasma membrane following synthesis. Half-helices and pore-lining regions in turn form functional ion channels and/or facilitate passive steroid uptake into the cell. In perspective, steroid-dependent insertion of "classical" receptors containing pore-lining regions into the plasma membrane may regulate permeability to ions such as Ca(2+), Na(+) or K(+), as well as facilitate steroid translocation into the nucleus.

No MeSH data available.