Na+/H+ exchanger: proton modifier site regulation of activity

1998 ◽  
Vol 76 (5) ◽  
pp. 743-749 ◽  
Author(s):  
James L Kinsella ◽  
Phillip Heller ◽  
Jeffrey P Froehlich
Keyword(s):  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Transition Rates ◽  
Extrinsic Factors ◽  
Pharmacological Agents ◽  
Protein Conformational Changes ◽  
Regulation Of Activity ◽  
Ph Dependent ◽  
Second Messenger Pathways ◽  
Exchange Activity

The Na+/H+ exchangers (NHE1-6) are integral plasma membrane proteins that catalyze the exchange of extracellular Na+ for intracellular H+. In addition to Na+ and H+ transport sites, NHE has an intracellular allosteric H+ modifier site that increases exchange activity when occupied by H+. NHE activity is also subject to control by a variety of extrinsic factors including hormones, growth factors, cytokines, and pharmacological agents. Many of these factors, working through second messenger pathways acting directly or indirectly on NHE, regulate NHE activity by shifting the apparent affinity of the H+ modifier site to more alkaline or more acid pH. The underlying molecular mechanisms involved in the activation of NHE by the H+ modifier site are poorly understood at this time, but likely involve slow protein conformational changes within a NHE oligomer. In this paper, we present initial experiments measuring intracellular pH-dependent transition rates between active and inactive oligomeric conformations and describe how these transition rates may be important for overall regulation of NHE activity.Key words: Na+/H+ exchangers, oligomers, hysteresis.

scholarly journals Mechanotransduction in tumor progression: The dark side of the force

2018 ◽  
Vol 217 (5) ◽  
pp. 1571-1587 ◽  
Author(s):  
Florence Broders-Bondon ◽  
Thanh Huong Nguyen Ho-Bouldoires ◽  
Maria-Elena Fernandez-Sanchez ◽  
Emmanuel Farge
Keyword(s):  
Cell Cycle ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Hydrodynamic Pressure ◽  
Dark Side ◽  
Mesenchymal Transition ◽  
Biochemical Pathways ◽  
Protein Conformational Changes ◽  
Tumor Tissues

Cancer has been characterized as a genetic disease, associated with mutations that cause pathological alterations of the cell cycle, adhesion, or invasive motility. Recently, the importance of the anomalous mechanical properties of tumor tissues, which activate tumorigenic biochemical pathways, has become apparent. This mechanical induction in tumors appears to consist of the destabilization of adult tissue homeostasis as a result of the reactivation of embryonic developmental mechanosensitive pathways in response to pathological mechanical strains. These strains occur in many forms, for example, hypervascularization in late tumors leads to high static hydrodynamic pressure that can promote malignant progression through hypoxia or anomalous interstitial liquid and blood flow. The high stiffness of tumors directly induces the mechanical activation of biochemical pathways enhancing the cell cycle, epithelial–mesenchymal transition, and cell motility. Furthermore, increases in solid-stress pressure associated with cell hyperproliferation activate tumorigenic pathways in the healthy epithelial cells compressed by the neighboring tumor. The underlying molecular mechanisms of the translation of a mechanical signal into a tumor inducing biochemical signal are based on mechanically induced protein conformational changes that activate classical tumorigenic signaling pathways. Understanding these mechanisms will be important for the development of innovative treatments to target such mechanical anomalies in cancer.

Coarse-Grained Molecular Dynamics Simulations of Sugar Transport Across Lactose Permease

2015 ◽  
Author(s):  
Yead Jewel ◽  
Prashanta Dutta ◽  
Jin Liu
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Active Transport ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Sugar Transport ◽  
Potential Of Mean Force ◽  
Coarse Grained ◽  
Lactose Permease ◽  
Protein Conformational Changes

Sugar (one of the critical nutrition elements for all life forms) transport across the cell membranes play essential roles in a wide range of living organism. One of the most important active transport (against the sugar concentration) mechanisms is facilitated by the transmembrane transporter proteins, such as the Escherichia coli lactose permease (LacY) proteins. Active transport of sugar molecules with LacY proteins requires a proton gradient and a sequence of complicated protein conformational changes. However, the exact molecular mechanisms and the protein structural information involved in the transport process are largely unknown. All atom atomistic simulations are able to provide full details but are limited to relative small length and time scales due to the computational cost. The protein conformational changes during sugar transport across LacY are large scale structural reorganization and inaccessible to all atom simulations. In this work, we investigate the molecular mechanisms and conformational changes during sugar transport using coarse-grained molecular dynamics (CGMD) simulations. In our coarse-grained force field, we follow the procedures developed by Han et al. [1, 2], in which the protein model is united-atom based and each heavy atom together with the attached hydrogen atoms is represented by one site, then the protein force filed is coupled with the MARTINI [3] water and lipid force fields. This hybrid force field takes the advantage of the efficiency of MARTINI force field for the environment (water and lipid), while retaining the detailed conformational information for the proteins. Specifically, we develop the new force fields for interactions between sugar molecules and protein by matching the potential of mean force between all-atom and coarse-grained models. Then we validate our force field by comparing the potential of mean force for a glucose interaction with a carbohydrate binding protein from our new force field, with the results from all atom simulations. After validation, we implement the force field for sugar transport across LacY proteins. Through our simulations we are able to capture the formation/breakage of the important hydrogen bonds and salt bridges, which are crucial to the overall conformational changes of LacY.

Temperature- and pH-dependent protein conformational changes investigated by terahertz dielectric spectroscopy

2019 ◽  
Vol 98 ◽  
pp. 260-265 ◽  
Author(s):  
Ziyi Zang ◽  
Shihan Yan ◽  
Xiaohui Han ◽  
Dongshan Wei ◽  
Hong-Liang Cui ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Dielectric Spectroscopy ◽  
Protein Conformational Changes ◽  
Dependent Protein ◽  
Ph Dependent

scholarly journals Interactions of urdine diphosphate glucose dehydrogenase with the inhibitor urdine diphosphate xylose

1975 ◽  
Vol 145 (2) ◽  
pp. 129-134 ◽  
Author(s):  
P A Gainey ◽  
C F Phelps
Keyword(s):  
Conformational Changes ◽  
Protein Concentration ◽  
Protein Modification ◽  
Fluorescence Enhancement ◽  
Glucose Dehydrogenase ◽  
Protein Fluorescence ◽  
Low Protein ◽  
Protein Conformational Changes ◽  
Diphosphate Glucose ◽  
Ph Dependent

1. UDP-xylose and UDP-glucose both bind to UDP-glucose dehydrogenase in the absence of NAD+, causing an enhancement of protein fluorescence. 2. The binding of UDP-xylose is pH-dependent, tighter binding being observed at pH8.2 than at pH8.7. 3. At low protein concentrations sigmiodal profiles of fluorescence enhancement are obtained on titration of the enzyme with UDP-xylose. As the protein concentration is increased the titration profiles become progressively more hypebolic in shape. 4. The markedly different titration profiles obtained on titrating enzyme and the enzyme-NAD+ complex with UDP-xylose suggests a conformational difference between these two species 5. NAD+ lowere the apparent affinity of the enzyme for UDP-xylose. 6. There is no change in the apparent moleculare weight of UDP-glucose dehydrogenase on binging UDP-xylose. 7. Protein modification by either diethyl pyrocarbonate or 5, 5′-dithiobis-(2-nitrobenzoate) does not “desensitize” the enzyme with respect to the inhibition by UDP-xylose. 8. UDP-xylose lowers the affinity of the enzyme for NADG. 9. It is suggested that UDP-xylose is acting as a substrate analogue of UDP-glucose and causes protein-conformational changes on binding to the enzyme.

pH-Dependent Thermal Stability of Vibrio cholerae L-asparaginase

2019 ◽  
Vol 26 (10) ◽  
pp. 743-750 ◽  
Author(s):  
Remya Radha ◽  
Sathyanarayana N. Gummadi
Keyword(s):  
Vibrio Cholerae ◽  
Conformational Changes ◽  
Kinetic Studies ◽  
Structural Features ◽  
Structure Stability ◽  
Kcal Mole ◽  
Scanning Calorimetry ◽  
Wide Range ◽  
Ph Dependent ◽  
Ph Range

Background:pH is one of the decisive macromolecular properties of proteins that significantly affects enzyme structure, stability and reaction rate. Change in pH may protonate or deprotonate the side group of aminoacid residues in the protein, thereby resulting in changes in chemical and structural features. Hence studies on the kinetics of enzyme deactivation by pH are important for assessing the bio-functionality of industrial enzymes. L-asparaginase is one such important enzyme that has potent applications in cancer therapy and food industry.Objective:The objective of the study is to understand and analyze the influence of pH on deactivation and stability of Vibrio cholerae L-asparaginase.Methods:Kinetic studies were conducted to analyze the effect of pH on stability and deactivation of Vibrio cholerae L-asparaginase. Circular Dichroism (CD) and Differential Scanning Calorimetry (DSC) studies have been carried out to understand the pH-dependent conformational changes in the secondary structure of V. cholerae L-asparaginase.Results:The enzyme was found to be least stable at extreme acidic conditions (pH< 4.5) and exhibited a gradual increase in melting temperature from 40 to 81 °C within pH range of 4.0 to 7.0. Thermodynamic properties of protein were estimated and at pH 7.0 the protein exhibited ΔG37of 26.31 kcal mole-1, ΔH of 204.27 kcal mole-1 and ΔS of 574.06 cal mole-1 K-1.Conclusion:The stability and thermodynamic analysis revealed that V. cholerae L-asparaginase was highly stable over a wide range of pH, with the highest stability in the pH range of 5.0–7.0.

scholarly journals Protein conformational changes and myelin solubilization by anion-detergent solutions

FEBS Letters ◽  
1992 ◽  
Vol 309 (3) ◽  
pp. 376-380 ◽  
Author(s):  
Jaime Monreal ◽  
Pedro Carmona ◽  
Pilar Regueiro ◽  
Ricardo S. Diaz
Keyword(s):  
Conformational Changes ◽  
Protein Conformational Changes ◽  
Detergent Solutions
Sign in / Sign up

Export Citation Format

Share Document