Molecular Dynamics Simulation Studies of GLUT4: Substrate-Free and Substrate-Induced Dynamics and ATP-Mediated Glucose Transport Inhibition

BACKGROUND: Glucose transporter 4 (GLUT4) is an insulin facilitated glucose transporter that plays an important role in maintaining blood glucose homeostasis. GLUT4 is sequestered into intracellular vesicles in unstimulated cells and translocated to the plasma membrane by various stimuli. Understanding the structural details of GLUT4 will provide insights into the mechanism of glucose transport and its regulation. To date, a crystal structure for GLUT4 is not available. However, earlier work from our laboratory proposed a well validated homology model for GLUT4 based on the experimental data available on GLUT1 and the crystal structure data obtained from the glycerol 3-phosphate transporter. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, the dynamic behavior of GLUT4 in a membrane environment was analyzed using three forms of GLUT4 (apo, substrate and ATP-substrate bound states). Apo form simulation analysis revealed an extracellular open conformation of GLUT4 in the membrane favoring easy exofacial binding of substrate. Simulation studies with the substrate bound form proposed a stable state of GLUT4 with glucose, which can be a substrate-occluded state of the transporter. Principal component analysis suggested a clockwise movement for the domains in the apo form, whereas ATP substrate-bound form induced an anti-clockwise rotation. Simulation studies suggested distinct conformational changes for the GLUT4 domains in the ATP substrate-bound form and favor a constricted behavior for the transport channel. Various inter-domain hydrogen bonds and switching of a salt-bridge network from E345-R350-E409 to E345-R169-E409 contributed to this ATP-mediated channel constriction favoring substrate occlusion and prevention of its release into cytoplasm. These data are consistent with the biochemical studies, suggesting an inhibitory role for ATP in GLUT-mediated glucose transport. CONCLUSIONS/SIGNIFICANCE: In the absence of a crystal structure for any glucose transporter, this study provides mechanistic details of the conformational changes in GLUT4 induced by substrate and its regulator

Some observations on the beaked sea snake Enhydrina schistosa (Daudin, 1803) in the mudbank area, off Alapuzha, Kerala, southwest coast of India

Hook-nosed sea snake or beaked snake, Enhydrina schistosa were caught during experimental fishing operations in the mudbank region along central Kerala Coast at depths ranging from 6 to 12 m. The sea snakes were found to form aggregations of 5 to 6 numbers and were able to tolerate highly turbid waters. The catfish Arius jella and the puffer fish Lagocephalus inermis were the dominant prey items. mudbanks are unusually calm areas which form along the Kerala coast during the monsoon. The inshore waters including the mudbanks are intense fishing areas of non mechanized crafts during the monsoon. The presence of venomous sea snakes is precarious and there is a need to give awareness programme for the fishers about this danger

Marine litter - A problem for stake net fishers: A case study in Vembanad Lake, Kerala

Plastics have becom e an inevitable item in daily life. Since they are non -deg rad able and persist fo r cen tau ries th ey are conside red as one o f the m ost serious th rea ts to the m a rine ecosystem in the cu rren t cen tu ry. M a rine litte r consisting o f plastics and o th e r non -biod eg rad able m aterial reach th e sea th ro ug h rivers and estuaries due to im p rop e r disposal o r som e tim es are discarded directly into the ecosystem . Th e coastal w a te rs are im p o rtan t fishing areas w h e re tradition al fish e rm en use diffe ren t types o f c ra ft and gea r to h a rvest the fish from the na tu ral w a te rs. The prog ressive increase in plastics and th eir indisc rim in a te discards have a ffected the ecosystem and also th e fish e rs w h o depend on the ecosystem

Anisotropic critical currents in FeSe0.5Te0.5 films and the influence of neutron irradiation

We report on measurements of the superconducting properties of FeSe05Te05 thin films grown on lanthanum aluminate. The films have high transition temperatures (above 19 K) and sharp resistive transitions in fields up to 15 T. The temperature dependence of the upper critical field and the irreversibility lines are steep and anisotropic, as recently reported for single crystals. The critical current densities, assessed by magnetization measurements in a vector VSM, were found to be well above 10^9 Am-2 at low temperatures. In all samples, the critical current as a function of field orientation has a maximum, when the field is oriented parallel to the film surface. The maximum indicates the presence of correlated pinning centers. A minimum occurs in three films, when the field is applied perpendicular to the film plane. In the forth film, instead, a local maximum caused by c-axis correlated pinning centers was found at this orientation. The irradiation of two films with fast neutrons did not change the properties drastically, where a maximum enhancement of the critical current by a factor of two was found

Thin Film Growth and Device Fabrication of Iron-Based Superconductors

Iron-based superconductors have received much attention as a new family of high-temperature superconductors owing to their unique properties and distinct differences from cuprates and conventional superconductors. This paper reviews progress in thin film research on iron-based superconductors since their discovery for each of five material systems with an emphasis on growth, physical properties, device fabrication, and relevant bulk material properties.Comment: To appear in J. Phys. Soc. Jp

Determination of Dynamic Mechanical Properties on Addition of Carbon Black-Nanosilica Hybrid Fillers in NR-SBR Blends with Special Reference to Power Transmission Belt Applications

Next to tyres, power transmission belts are one of the most complicated rubber products which is having a constant increase for demand in the market. Due to this high demand along with the requirement to meet certain special operating conditions, it is necessary to improve the belt properties continuously. In the last few decades, nanotechnology evolved as a suitable method for enhancing the properties of various rubber products without impacting the environment. Nanofillers which are having unique morphology along with excellent properties help to reduce the dependency in petroleum products and in turn make the products more sustainable. Even though, studies related to the usage of nanotechnology in the power transmission belt division are very limited. So, in this study, the effect of nanosilica on the dynamic mechanical properties of the natural rubber- (NR-) styrene butadiene rubber (SBR) blends is thoroughly studied with special reference to power transmission belt applications. The developed composites were analysed to ensure the rheological, mechanical, and morphological properties in comparison with the controlled samples. The nanosilica-based belt properties were analysed in reference with regular carbon black-filled belts, and a 15% improvement in belt life was obtained for newly developed belts

Elucidation of the glucose transport pathway in glucose transporter 4 via steered molecular dynamics simulations.

BACKGROUND: GLUT4 is a predominant insulin regulated glucose transporter expressed in major glucose disposal tissues such as adipocytes and muscles. Under the unstimulated state, GLUT4 resides within intracellular vesicles. Various stimuli such as insulin translocate this protein to the plasma membrane for glucose transport. In the absence of a crystal structure for GLUT4, very little is known about the mechanism of glucose transport by this protein. Earlier we proposed a homology model for GLUT4 and performed a conventional molecular dynamics study revealing the conformational rearrangements during glucose and ATP binding. However, this study could not explain the transport of glucose through the permeation tunnel. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the molecular mechanism of glucose transport and its energetic, a steered molecular dynamics study (SMD) was used. Glucose was pulled from the extracellular end of GLUT4 to the cytoplasm along the pathway using constant velocity pulling method. We identified several key residues within the tunnel that interact directly with either the backbone ring or the hydroxyl groups of glucose. A rotation of glucose molecule was seen near the sugar binding site facilitating the sugar recognition process at the QLS binding site. CONCLUSIONS/SIGNIFICANCE: This study proposes a possible glucose transport pathway and aids the identification of several residues that make direct interactions with glucose during glucose transport. Mutational studies are required to further validate the observation made in this study

Not Available

Not AvailableHook-nosed sea snake or beaked snake, Enhydrina schistosa were caught during experimental fishing operations in the mudbank region along central Kerala Coast at depths ranging from 6 to 12 m. The sea snakes were found to form aggregations of 5 to 6 numbers and were able to tolerate highly turbid waters. The catfish Arius jella and the puffer fish Lagocephalus inermis were the dominant prey items. mudbanks are unusually calm areas which form along the Kerala coast during the monsoon. The inshore waters including the mudbanks are intense fishing areas of non mechanized crafts during the monsoon. The presence of venomous sea snakes is precarious and there is a need to give awareness programme for the fishers about this danger.Not Availabl

Not Available

Not AvailableHook-nosed sea snake or beaked snake, Enhydrina schistosa were caught during experimental fishing operations in the mudbank region along central Kerala Coast at depths ranging from 6 to 12 m. The sea snakes were found to form aggregations of 5 to 6 numbers and were able to tolerate highly turbid waters. The catfish Arius jella and the puffer fish Lagocephalus inermis were the dominant prey items. mudbanks are unusually calm areas which form along the Kerala coast during the monsoon. The inshore waters including the mudbanks are intense fishing areas of non mechanized crafts during the monsoon. The presence of venomous sea snakes is precarious and there is a need to give awareness programme for the fishers about this danger.Not Availabl