scholarly journals Transmembrane Helices in “Classical” Nuclear Reproductive Steroid Receptors: A Perspective

2015 ◽  
Vol 13 (1) ◽  
pp. nrs.13003 ◽  
Author(s):  
Gene A. Morrill ◽  
Adele B. Kostellow ◽  
Raj K. Gupta
Keyword(s):  
Plasma Membrane ◽  
Steroid Receptors ◽  
Transmembrane Helices ◽  
X Ray ◽  
Binding Domains ◽  
Steroid Dependent ◽  
Svm Algorithm ◽  
Specific Receptors ◽  
Pore Lining ◽  
Free Steroid

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 Ca2+, Na+ or K+, as well as facilitate steroid translocation into the nucleus.

scholarly journals Structure of a 14-3-3 Coordinated Hexamer of the Plant Plasma Membrane H+-ATPase by Combining X-Ray Crystallography and Electron Cryomicroscopy

2007 ◽  
Vol 25 (3) ◽  
pp. 427-440 ◽  
Author(s):  
Christian Ottmann ◽  
Sergio Marco ◽  
Nina Jaspert ◽  
Caroline Marcon ◽  
Nicolas Schauer ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Electron Cryomicroscopy ◽  
X Ray ◽  
X Ray Crystallography ◽  
Plant Plasma Membrane

Ligand modulates the conversion of DNA-bound vitamin D3 receptor (VDR) homodimers into VDR-retinoid X receptor heterodimers

1994 ◽  
Vol 14 (5) ◽  
pp. 3329-3338
Author(s):  
B Cheskis ◽  
L P Freedman
Keyword(s):  
Ligand Binding ◽  
Vitamin D3 ◽  
Hormone Receptors ◽  
Steroid Receptors ◽  
Dependent Manner ◽  
D3 Receptor ◽  
Vitamin D3 Receptor ◽  
Binding Domains

Protein dimerization facilitates cooperative, high-affinity interactions with DNA. Nuclear hormone receptors, for example, bind either as homodimers or as heterodimers with retinoid X receptors (RXR) to half-site repeats that are stabilized by protein-protein interactions mediated by residues within both the DNA- and ligand-binding domains. In vivo, ligand binding among the subfamily of steroid receptors unmasks the nuclear localization and DNA-binding domains from a complex with auxiliary factors such as the heat shock proteins. However, the role of ligand is less clear among nuclear receptors, since they are constitutively localized to the nucleus and are presumably associated with DNA in the absence of ligand. In this study, we have begun to explore the role of the ligand in vitamin D3 receptor (VDR) function by examining its effect on receptor homodimer and heterodimer formation. Our results demonstrate that VDR is a monomer in solution; VDR binding to a specific DNA element leads to the formation of a homodimeric complex through a monomeric intermediate. We find that 1,25-dihydroxyvitamin D3, the ligand for VDR, decreases the amount of the DNA-bound VDR homodimer complex. It does so by significantly decreasing the rate of conversion of DNA-bound monomer to homodimer and at the same time enhancing the dissociation of the dimeric complex. This effectively stabilizes the bound monomeric species, which in turn serves to favor the formation of a VDR-RXR heterodimer. The ligand for RXR, 9-cis retinoic acid, has the opposite effect of destabilizing the heterodimeric-DNA complex. These results may explain how a nuclear receptor can bind DNA constitutively but still act to regulate transcription in a fully hormone-dependent manner.

scholarly journals The primary structural photoresponse of phytochrome proteins captured by a femtosecond X-ray laser

2019 ◽  
Author(s):  
Elin Claesson ◽  
Weixiao Yuan Wahlgren ◽  
Heikki Takala ◽  
Suraj Pandey ◽  
Leticia Castillon ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Structural Changes ◽  
Red Light ◽  
Crystallographic Data ◽  
Water Dissociation ◽  
X Ray ◽  
Binding Domains ◽  
Delay Times

Phytochrome proteins control the growth, reproduction, and photosynthesis of plants, fungi, and bacteria. Light is detected by a bilin cofactor, but it remains elusive how this leads to activation of the protein through structural changes. We present serial femtosecond X-ray crystallographic data of the chromophore-binding domains of a bacterial phytochrome at delay times of 1 ps and 10 ps after photoexcitation. The structures reveal a twist of the D-ring, which lead to partial detachment of the chromophore from the protein. Unexpectedly, the conserved so-called pyrrole water is photodissociated from the chromophore, concomitant with movement of the A-ring and a key signalling aspartate. The changes are wired together by ultrafast backbone and water movements around the chromophore, channeling them into signal transduction towards the output domains. We suggest that the water dissociation is key to the phytochrome photoresponse, explaining the earliest steps of how plants, fungi and bacteria sense red light.

scholarly journals Crystallization and preliminary X-ray analysis of a complex of the FOXO1 and Ets1 DNA-binding domains and DNA

2013 ◽  
Vol 70 (1) ◽  
pp. 44-48 ◽  
Author(s):  
Wing W. Choy ◽  
Drishadwatti Datta ◽  
Catherine A. Geiger ◽  
Gabriel Birrane ◽  
Marianne A. Grant
Keyword(s):  
Dna Binding ◽  
X Ray ◽  
Dna Binding Domains ◽  
Binding Domains

scholarly journals Num1 anchors mitochondria to the plasma membrane via two domains with different lipid binding specificities

2016 ◽  
Vol 213 (5) ◽  
pp. 513-524 ◽  
Author(s):  
Holly A. Ping ◽  
Lauren M. Kraft ◽  
WeiTing Chen ◽  
Amy E. Nilles ◽  
Laura L. Lackner
Keyword(s):  
Plasma Membrane ◽  
Specific Binding ◽  
Coiled Coil ◽  
Lipid Binding ◽  
General Mechanism ◽  
Cell Cortex ◽  
Pleckstrin Homology Domain ◽  
Binding Domains ◽  
Coiled Coil Domain ◽  
Mitochondrial Distribution

The mitochondria–ER cortex anchor (MECA) is required for proper mitochondrial distribution and functions by tethering mitochondria to the plasma membrane. The core component of MECA is the multidomain protein Num1, which assembles into clusters at the cell cortex. We show Num1 adopts an extended, polarized conformation. Its N-terminal coiled-coil domain (Num1CC) is proximal to mitochondria, and the C-terminal pleckstrin homology domain is associated with the plasma membrane. We find that Num1CC interacts directly with phospholipid membranes and displays a strong preference for the mitochondria-specific phospholipid cardiolipin. This direct membrane interaction is critical for MECA function. Thus, mitochondrial anchoring is mediated by a protein that interacts directly with two different membranes through lipid-specific binding domains, suggesting a general mechanism for interorganelle tethering.

scholarly journals Crystal structure of a human plasma membrane phospholipid flippase

2020 ◽  
Vol 295 (30) ◽  
pp. 10180-10194 ◽  
Author(s):  
Hanayo Nakanishi ◽  
Katsumasa Irie ◽  
Katsumori Segawa ◽  
Kazuya Hasegawa ◽  
Yoshinori Fujiyoshi ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Human Plasma ◽  
Binding Sites ◽  
The Other ◽  
Asymmetric Distribution ◽  
Transmembrane Helices ◽  
Outer Leaflet ◽  
Extracellular Side ◽  
Phospholipid Flippase ◽  
Plasma Membrane Phospholipid

ATP11C, a member of the P4-ATPase flippase, translocates phosphatidylserine from the outer to the inner plasma membrane leaflet, and maintains the asymmetric distribution of phosphatidylserine in the living cell. We present the crystal structures of a human plasma membrane flippase, ATP11C–CDC50A complex, in a stabilized E2P conformation. The structure revealed a deep longitudinal crevice along transmembrane helices continuing from the cell surface to the phospholipid occlusion site in the middle of the membrane. We observed that the extension of the crevice on the exoplasmic side is open, and the complex is therefore in an outward-open E2P state, similar to a recently reported cryo-EM structure of yeast flippase Drs2p–Cdc50p complex. We noted extra densities, most likely bound phosphatidylserines, in the crevice and in its extension to the extracellular side. One was close to the phosphatidylserine occlusion site as previously reported for the human ATP8A1–CDC50A complex, and the other in a cavity at the surface of the exoplasmic leaflet of the bilayer. Substitutions in either of the binding sites or along the path between them impaired specific ATPase and transport activities. These results provide evidence that the observed crevice is the conduit along that phosphatidylserine traverses from the outer leaflet to its occlusion site in the membrane and suggest that the exoplasmic cavity is important for phospholipid recognition. They also yield insights into how phosphatidylserine is incorporated from the outer leaflet of the plasma membrane into the transmembrane.

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