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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.


Androgen receptor.Topology of TM helices and pore-lining regions of Homo sapiens classical androgen receptor (ARB, P102750), comparing the MemBrain algorithm (upper plot), the TOPCONS consensus method (middle plot) and MEMSAT-SVM method (lower plot). Blue squares in the MEMSAT-SVM projection indicate predicted pore-lining regions. See Methods.
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f1: Androgen receptor.Topology of TM helices and pore-lining regions of Homo sapiens classical androgen receptor (ARB, P102750), comparing the MemBrain algorithm (upper plot), the TOPCONS consensus method (middle plot) and MEMSAT-SVM method (lower plot). Blue squares in the MEMSAT-SVM projection indicate predicted pore-lining regions. See Methods.

Mentions: Figure 1 compares the propensity of TM helix formation in ARB using three current algorithms: the MemBrain method (top), TOPCONS consensus method (middle) and MEMSAT-SVM method (bottom). All methods predict one or more TM helices or pore-lining regions in the C-terminal region. Similar analyses of ER1and PRB are shown in Figure 2 and Figure 3, respectively. As shown for ARB, ER1 and PRB, both the TOPCONS [Bernsel et al., 2009] and MemBrain [Shen and Chou, 2008] methods predict a TM helix pair in the C-terminal region of each “classical” receptor. Analysis of ER2 demonstrates a single TM helix in the C-terminal region (not shown).


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

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

Androgen receptor.Topology of TM helices and pore-lining regions of Homo sapiens classical androgen receptor (ARB, P102750), comparing the MemBrain algorithm (upper plot), the TOPCONS consensus method (middle plot) and MEMSAT-SVM method (lower plot). Blue squares in the MEMSAT-SVM projection indicate predicted pore-lining regions. See Methods.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Androgen receptor.Topology of TM helices and pore-lining regions of Homo sapiens classical androgen receptor (ARB, P102750), comparing the MemBrain algorithm (upper plot), the TOPCONS consensus method (middle plot) and MEMSAT-SVM method (lower plot). Blue squares in the MEMSAT-SVM projection indicate predicted pore-lining regions. See Methods.
Mentions: Figure 1 compares the propensity of TM helix formation in ARB using three current algorithms: the MemBrain method (top), TOPCONS consensus method (middle) and MEMSAT-SVM method (bottom). All methods predict one or more TM helices or pore-lining regions in the C-terminal region. Similar analyses of ER1and PRB are shown in Figure 2 and Figure 3, respectively. As shown for ARB, ER1 and PRB, both the TOPCONS [Bernsel et al., 2009] and MemBrain [Shen and Chou, 2008] methods predict a TM helix pair in the C-terminal region of each “classical” receptor. Analysis of ER2 demonstrates a single TM helix in the C-terminal region (not shown).

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.