Morrill Gene A, Kostellow Adele B, Gupta Raj K
Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461 USA.
Nucl Recept Signal. 2015 Jul 21;13:e003. doi: 10.1621/nrs.13003. eCollection 2015.
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.
1）位于胞质溶胶中，激活后转移至细胞核；2）与质膜内侧相连；3）保留在细胞核中，直到游离的类固醇激素进入并激活特定受体。通过计算方法分析肽受体拓扑结构，我们发现孕酮（PRB/PGR）、雄激素（ARB/AR）和雌激素（ER1/ESR1）的“经典”核受体在其配体结合域（LBD）内含有两个跨膜螺旋（TMH）。MEMSAT-SVM算法表明，ARB和ER2（但不是PRB或ER1）含有一个孔内衬（通道形成）区域，该区域可能与其他孔内衬区域合并形成膜通道。ER2缺乏TMH，但含有一个单一的孔内衬区域。MemBrain算法预测，PRB、ARB和ER1各自含有一个TMH加上一个由51个氨基酸隔开的半个TMH。ER2含有两个半螺旋。ARB、ER1和ER2的TM-2螺旋各自含有9-13个据报道可将受体转运至质膜的氨基酸基序以及半胱氨酸棕榈酰化位点。对X射线晶体学数据的PoreWalker分析在ARB和ER1的LBD内识别出一个孔或通道，并预测分别有70和72个残基是孔内衬残基。数据表明（ER2除外），胞质受体在合成后锚定在质膜上。半螺旋和孔内衬区域依次形成功能性离子通道和/或促进类固醇被动摄取进入细胞。从这个角度来看，含有孔内衬区域的“经典”受体的类固醇依赖性插入质膜可能调节对Ca(2+)、Na(+)或K(+)等离子的通透性，并促进类固醇转运至细胞核。
