Structure and function of aquaporin water channels

2000 ◽  
Vol 278 (1) ◽  
pp. F13-F28 ◽  
Author(s):  
A. S. Verkman ◽  
Alok K. Mitra
Keyword(s):  
High Throughput Screening ◽  
Plasma Membranes ◽  
Fluid Transport ◽  
Freeze Fracture ◽  
Structure And Function ◽  
Membrane Spanning ◽  
Definition Of ◽  
Protein Density ◽  
Basic Features ◽  
And Function

The aquaporins (AQPs) are a family of small membrane-spanning proteins (monomer size ∼30 kDa) that are expressed at plasma membranes in many cells types involved in fluid transport. This review is focused on the molecular structure and function of mammalian aquaporins. Basic features of aquaporin structure have been defined using mutagenesis, epitope tagging, and spectroscopic and freeze-fracture electron microscopy methods. Aquaporins appear to assemble in membranes as homotetramers in which each monomer, consisting of six membrane-spanning α-helical domains with cytoplasmically oriented amino and carboxy termini, contains a distinct water pore. Medium-resolution structural analysis by electron cryocrystallography indicated that the six tilted helical segments form a barrel surrounding a central pore-like region that contains additional protein density. Several of the mammalian aquaporins (e.g., AQP1, AQP2, AQP4, and AQP5) appear to be highly selective for the passage of water, whereas others (recently termed aquaglyceroporins) also transport glycerol (e.g., AQP3 and AQP8) and even larger solutes (AQP9). Evidence for possible movement of ions and carbon dioxide through the aquaporins is reviewed here, as well as evidence for direct regulation of aquaporin function by posttranslational modification such as phosphorylation. Important unresolved issues include definition of the molecular pathway through which water and solutes move, the nature of monomer-monomer interactions, and the physiological significance of aquaporin-mediated solute movement. Recent results from knockout mice implicating multiple physiological roles of aquaporins suggest that the aquaporins may be suitable targets for drug discovery by structure-based and/or high-throughput screening strategies.

scholarly journals Structure and Function of the CFTR Chloride Channel

1999 ◽  
Vol 79 (1) ◽  
pp. S23-S45 ◽  
Author(s):  
DAVID N. SHEPPARD ◽  
MICHAEL J. WELSH
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Channel ◽  
Atp Hydrolysis ◽  
Current Knowledge ◽  
Structure And Function ◽  
Binding Domains ◽  
Transporter Family ◽  
Membrane Spanning ◽  
And Function ◽  
R Domain

Sheppard, David N., and Michael J. Welsh. Structure and Function of the CFTR Chloride Channel. Physiol. Rev. 79 , Suppl.: S23–S45, 1999. — The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl− channel. It is located predominantly in the apical membrane of epithelia where it mediates transepithelial salt and liquid movement. Dysfunction of CFTR causes the genetic disease cystic fibrosis. The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. Here we review the structure and function of this unique channel, with a focus on how the various domains contribute to channel function. The MSDs form the channel pore, phosphorylation of the R domain determines channel activity, and ATP hydrolysis by the NBDs controls channel gating. Current knowledge of CFTR structure and function may help us understand better its mechanism of action, its role in electrolyte transport, its dysfunction in cystic fibrosis, and its relationship to other ABC transporters.

scholarly journals Effects of cytochalasin D on occluding junctions of intestinal absorptive cells: further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity.

1986 ◽  
Vol 102 (6) ◽  
pp. 2125-2136 ◽  
Author(s):  
J L Madara ◽  
D Barenberg ◽  
S Carlson
Keyword(s):  
Electron Microscopy ◽  
Freeze Fracture ◽  
Structure And Function ◽  
Cytochalasin D ◽  
Absorptive Cell ◽  
Absorptive Cells ◽  
Charge Selectivity ◽  
Occluding Junctions ◽  
And Function ◽  
Junction Structure

Intestinal absorptive cells may modulate both the structure and function of occluding junctions by a cytoskeleton dependent mechanism (Madara, J. L., 1983, J. Cell Biol., 97:125-136). To further examine the putative relationship between absorptive cell occluding junctions and the cytoskeleton, we assessed the effects of cytochalasin D (CD) on occluding junction function and structure in guinea pig ileum using ultrastructural and Ussing chamber techniques. Maximal decrements in transepithelial resistance and junctional charge selectivity were obtained with 10 micrograms/ml CD and the dose-response curves for these two functional parameters were highly similar. Analysis of simultaneous flux studies of sodium and the nonabsorbable extracellular tracer mannitol suggested that CD opened a transjunctional shunt and that this shunt could fully account for the increase in sodium permeability and thus the decrease in resistance. Structural studies including electron microscopy of detergent-extracted cytoskeletal preparations revealed that 10 micrograms/ml CD produced condensation of filamentous elements of the peri-junctional contractile ring and that this was associated with brush border contraction as assessed by scanning electron microscopy. Quantitative freeze-fracture studies revealed marked aberrations in absorptive cell occluding junction structure including diminished strand number, reduced strand-strand cross-linking, and failure of strands to impede the movement of intramembrane particles across them. In aggregate these studies show that CD-induced perturbation of the absorptive cell cytoskeleton results in production of a transepithelial shunt which is fully explained by a defect in the transjunctional pathway. Furthermore, substantial structural abnormalities in occluding junction structure accompany this response. Lastly, the abnormalities in occluding junction structure and function coincide with structural changes in and contraction of the peri-junctional actin-myosin ring. These data suggest that a functionally relevant association may exist between the cytoskeleton and the occluding junction of absorptive cells. We speculate that such an association may serve as a mechanism by which absorptive cells regulate paracellular transport.

scholarly journals The Conceptual Structure of Commercial Law

2020 ◽  
pp. 899
Author(s):  
Tamara M. Buckwold
Keyword(s):  
Conceptual Structure ◽  
Structure And Function ◽  
Commercial Law ◽  
Structural Framework ◽  
Legal Regimes ◽  
Rights And Interests ◽  
Definition Of ◽  
And Function

This article argues that commercial law is not merely a collection of rules, but a doctrinally coherent and conceptually sophisticated body of law structured through conceptions of property. The analysis focuses specifically on the aspects of commercial law that govern recovery of debt. The argument advances two related themes; that commercial law is built around conceptions of property and reciprocally defines the conceptions of property around which it is built. The article first addresses the role of property as the structural framework of commercial law. Property creates the basis for assertion of rights and provides the conceptual interface between the legal regimes of secured financing, judgment enforcement, and bankruptcy. Further, property is the basis on which commercial law rights and interests are reconciled with rights and interests that fall outside its boundaries. The article then explores the means by which commercial law resolves practical problems through the creative definition of property. The article concludes with thoughts on the importance of understanding the central role of property in the structure and function of commercial law.

scholarly journals Actin-binding compounds, discovered by FRET-based high-throughput screening, differentially affect skeletal and cardiac muscle

2020 ◽  
Author(s):  
Piyali Guhathakurta ◽  
Lien A. Phung ◽  
Ewa Prochniewicz ◽  
Sarah Lichtenberger ◽  
Anna Wilson ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Striated Muscle ◽  
Muscle Protein ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Structure And Function ◽  
Actin Binding ◽  
Myosin Isoforms ◽  
And Function

AbstractWe have used spectroscopic and functional assays to evaluate the effects of a group of actin-binding compounds on striated muscle protein structure and function. Actin is present in every human cell, and its interaction with multiple myosin isoforms and multiple actin-binding proteins is essential for cellular viability. A previous high-throughput time-resolved fluorescence resonance energy transfer (TR-FRET) assay from our group identified a class of compounds that bind to actin and affect actomyosin structure and function. In the current study, we tested their effects on the two isoforms of striated muscle α-actins, skeletal and cardiac. We found that a majority of these compounds affected the transition of monomeric G-actin to filamentous F-actin, and that these effects were different for the two actin isoforms, suggesting a different mode of action. To determine the effects of these compounds on sarcomeric function, we further tested their activity on skeletal and cardiac myofibrils. We found that several compounds affected ATPase activity of skeletal and cardiac myofibrils differently, suggesting different mechanisms of action of these compounds for the two muscle types. We conclude that these structural and biochemical assays can be used to identify actin-binding compounds that differentially affect skeletal and cardiac muscles. The results of this study set the stage for screening of large chemical libraries for discovery of novel compounds that act therapeutically and specifically on cardiac or skeletal muscle.

R&D Support Programs (the Need)

2017 ◽  
pp. 1-25
Keyword(s):  
Business Plan ◽  
Structure And Function ◽  
Support Program ◽  
Support Programs ◽  
Legal Environment ◽  
Support Tools ◽  
Different Types ◽  
Strategic Role ◽  
Definition Of ◽  
And Function

Any good business plan starts with the definition of the need for which it intends to base the entire business. Following that example, the discussion here should also start with the need for such programs, their strategic role as defined by research, and the rationale that makes them prevalent. When discussing R&D support programs, one needs to bear in mind that there are different types of such programs. The specific needs such programs were designed to answer, whether well or less so, the target audience or clients they address, and the specific legal environment they operate in, influence the different types and give rise to the need for different types of programs to begin with. In this chapter, we shall define the R&D support program and analyze examples of the influence the parameters mentioned above, have on the structure and function of the programs. The different types as well as support tools will be discussed at a later chapter (Chapter 05 – R&D support program types).

scholarly journals Structure and Function of the Plasma Membrane

1968 ◽  
Vol 52 (1) ◽  
pp. 257-278 ◽  
Author(s):  
Edward D. Korn
Keyword(s):  
Plasma Membrane ◽  
Plasma Membranes ◽  
Current Knowledge ◽  
Structure And Function ◽  
Attractive Alternative ◽  
Membrane Function ◽  
Classical Models ◽  
And Function ◽  
Direct Attack ◽  
Membrane Biosynthesis

The paucimolecular unit membrane model of the structure of the plasma membrane is critically reviewed in relation to current knowledge of the chemical and enzymatic composition of isolated plasma membranes, the properties of phospholipids, the chemistry of fixation for electron microscopy, the conformation of membrane proteins, the nature of the lipid-protein bonds in membranes, and possible mechanisms of transmembrane transport and membrane biosynthesis. It is concluded that the classical models, although not disproven, are not well supported by, and are difficult to reconcile with, the data now available. On the other hand, although a model based on lipoprotein subunits is, from a biochemical perspective, an attractive alternative, it too is far from proven. Many of the questions may be resolved by studies of membrane function and membrane biosynthesis rather than by a direct attack on membrane structure.

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