Role of protein matrix rigidity and local polarization effects in the monovalent cation selectivity of crystallographic sites in the Na-coupled aspartate transporter GltPh

2013 ◽  
Vol 15 (7) ◽  
pp. 2397 ◽  
Author(s):  
Bogdan Lev ◽  
Sergei Yu. Noskov
Keyword(s):  
Monovalent Cation ◽  
Matrix Rigidity ◽  
Protein Matrix ◽  
Polarization Effects ◽  
Cation Selectivity ◽  
Local Polarization

scholarly journals A Model for Predicting Cation Selectivity and Permeability in AMPA and NMDA Receptors Based on Receptor Subunit Composition

2021 ◽  
Vol 13 ◽  
Author(s):  
Sampath Kumar ◽  
Sanjay S. Kumar
Keyword(s):  
Experimental Data ◽  
Divalent Cations ◽  
Ion Selectivity ◽  
Gene Families ◽  
Subunit Composition ◽  
Receptor Subunit ◽  
Cation Selectivity ◽  
Subunit Stoichiometry ◽  
Ampa And Nmda Receptors

Glutamatergic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) receptors are implicated in diverse functions ranging from synaptic plasticity to cell death. They are heterotetrameric proteins whose subunits are derived from multiple distinct gene families. The subunit composition of these receptors determines their permeability to monovalent and/or divalent cations, but it is not entirely clear how this selectivity arises in native and recombinantly-expressed receptor populations. By analyzing the sequence of amino acids lining the selectivity filters within the pore forming membrane helices (M2) of these subunits and by correlating subunit stoichiometry of these receptors with their ability to permeate Na+ and/or Ca2+, we propose here a mathematical model for predicting cation selectivity and permeability in these receptors. The model proposed is based on principles of charge attractivity and charge neutralization within the pore forming region of these receptors; it accurately predicts and reconciles experimental data across various platforms including Ca2+ permeability of GluA2-lacking AMPARs and ion selectivity within GluN3-containing di- and tri-heteromeric NMDARs. Additionally, the model provides insights into biophysical mechanisms regulating cation selectivity and permeability of these receptors and the role of various subunits in these processes.

scholarly journals Tuning the ion selectivity of glutamate transporter–associated uncoupled conductances

2016 ◽  
Vol 148 (1) ◽  
pp. 13-24 ◽  
Author(s):  
Rosemary J. Cater ◽  
Robert J. Vandenberg ◽  
Renae M. Ryan
Keyword(s):  
Excitatory Amino Acid ◽  
Ion Selectivity ◽  
Glutamate Transporter ◽  
Amino Acid Transporters ◽  
Primary Role ◽  
Cation Selectivity ◽  
Anion Selectivity ◽  
Transport Domain ◽  
Cl Conductance

The concentration of glutamate within a glutamatergic synapse is tightly regulated by excitatory amino acid transporters (EAATs). In addition to their primary role in clearing extracellular glutamate, the EAATs also possess a thermodynamically uncoupled Cl− conductance. This conductance is activated by the binding of substrate and Na+, but the direction of Cl− flux is independent of the rate or direction of substrate transport; thus, the two processes are thermodynamically uncoupled. A recent molecular dynamics study of the archaeal EAAT homologue GltPh (an aspartate transporter from Pyrococcus horikoshii) identified an aqueous pore at the interface of the transport and trimerization domains, through which anions could permeate, and it was suggested that an arginine residue at the most restricted part of this pathway might play a role in determining anion selectivity. In this study, we mutate this arginine to a histidine in the human glutamate transporter EAAT1 and investigate the role of the protonation state of this residue on anion selectivity and transporter function. Our results demonstrate that a positive charge at this position is crucial for determining anion versus cation selectivity of the uncoupled conductance of EAAT1. In addition, because the nature of this residue influences the turnover rate of EAAT1, we reveal an intrinsic link between the elevator movement of the transport domain and the Cl− channel.

The role of monovalent cation/proton antiporters in Na(+)-resistance and pH homeostasis in Bacillus: an alkaliphile versus a neutralophile.

1994 ◽  
Vol 196 (1) ◽  
pp. 457-470 ◽  
Author(s):  
T A Krulwich ◽  
J Cheng ◽  
A A Guffanti
Keyword(s):  
Driving Forces ◽  
Monovalent Cation ◽  
Ph Homeostasis ◽  
Proton Extrusion ◽  
Gene Encoding ◽  
Internal Ph ◽  
Alkaliphilic Bacillus ◽  
Pronounced Reduction ◽  
External Ph

Both neutralophilic Bacillus subtilis and alkaliphilic Bacillus firmus OF4 depend upon electrogenic Na+/H+ antiporters, which are energized by the gradients established by respiration-coupled proton extrusion, to achieve Na(+)-resistance and pH homeostasis when the external pH is very alkaline. The interplay of proton and sodium cycles is discussed. In B. subtilis, pH homeostasis, up to pH9, can be achieved using K+ when Na+ is unavailable or when the gene encoding the Na+/H+ antiporter that is involved in Na(+)-dependent pH homeostasis is disrupted. That gene is a member of the tetracycline efflux family of genes. A second gene, encoding a Na+/H+ antiporter that functions in Na(+)-resistance, has been identified, and candidates for the K+/H+ antiporter genes are under investigation. Aggregate Na+/H+ antiport activity in B. subtilis is as much as 10 times lower than in the alkaliphile, and the neutralophile cannot regulate its internal pH upon a shift to pH 10.5. Upon such a shift, there is a pronounced reduction in the generation of a primary electrochemical proton gradient. The alkaliphile, by contrast, maintains substantial driving forces and regulates its internal pH in an exclusively Na(+)-coupled manner upon shifts to either pH 8.7 or 10.5. One gene locus has been identified and a second locus has been inferred as encoding relevant antiporter activities.

Elucidating factors important for monovalent cation selectivity in enzymes: E. coli β-galactosidase as a model

2015 ◽  
Vol 17 (16) ◽  
pp. 10899-10909 ◽  
Author(s):  
Robert W. Wheatley ◽  
Douglas H. Juers ◽  
Bogdan B. Lev ◽  
Reuben E. Huber ◽  
Sergei Yu. Noskov
Keyword(s):  
Monovalent Cation ◽  
Computational Simulations ◽  
X Ray ◽  
E Coli ◽  
X Ray Crystallography ◽  
Cation Selectivity

X-ray crystallography and computational simulations reveal novel mechanisms important for Na+/K+selectivity in enzymes.

scholarly journals Linking Extracellular Matrix Agrin to the Hippo Pathway in Liver Cancer and Beyond

Cancers ◽  
2018 ◽  
Vol 10 (2) ◽  
pp. 45 ◽  
Author(s):  
Sayan Chakraborty ◽  
Wanjin Hong
Keyword(s):  
Extracellular Matrix ◽  
Neuromuscular Junctions ◽  
Hippo Pathway ◽  
Cardiac Regeneration ◽  
Matrix Rigidity ◽  
Macroscopic Scale ◽  
Cellular Processes ◽  
Scale Matrix ◽  
The Hippo Pathway

In addition to the structural and scaffolding role, the extracellular matrix (ECM) is emerging as a hub for biomechanical signal transduction that is frequently relayed to intracellular sensors to regulate diverse cellular processes. At a macroscopic scale, matrix rigidity confers long-ranging effects contributing towards tissue fibrosis and cancer. The transcriptional co-activators YAP/TAZ, better known as the converging effectors of the Hippo pathway, are widely recognized for their new role as nuclear mechanosensors during organ homeostasis and cancer. Still, how YAP/TAZ senses these “stiffness cues” from the ECM remains enigmatic. Here, we highlight the recent perspectives on the role of agrin in mechanosignaling from the ECM via antagonizing the Hippo pathway to activate YAP/TAZ in the contexts of cancer, neuromuscular junctions, and cardiac regeneration.

scholarly journals The role of monovalent cations in the ATPase reaction of DNA gyrase

2015 ◽  
Vol 71 (4) ◽  
pp. 996-1005 ◽  
Author(s):  
Stephen James Hearnshaw ◽  
Terence Tsz-Hong Chung ◽  
Clare Elizabeth Mary Stevenson ◽  
Anthony Maxwell ◽  
David Mark Lawson
Keyword(s):  
Escherichia Coli ◽  
Binding Sites ◽  
Dna Gyrase ◽  
Monovalent Cation ◽  
Cation Binding ◽  
Monovalent Cations ◽  
Atpase Domain ◽  
Atpase Reaction ◽  
Resolution Structure

Four new crystal structures of the ATPase domain of the GyrB subunit ofEscherichia coliDNA gyrase have been determined. One of these, solved in the presence of K+, is the highest resolution structure reported so far for this domain and, in conjunction with the three other structures, reveals new insights into the function of this domain. Evidence is provided for the existence of two monovalent cation-binding sites: site 1, which preferentially binds a K+ion that interacts directly with the α-phosphate of ATP, and site 2, which preferentially binds an Na+ion and the functional significance of which is not clear. The crystallographic data are corroborated by ATPase data, and the structures are compared with those of homologues to investigate the broader conservation of these sites.

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