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What is internal symmetry in membrane proteins?

What is internal symmetry in membrane proteins?


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I have come across the term "internal symmetry" in the context of membrane proteins, but have never found a satisfactory definition.

I'm struggling to figure out exactly what this term means… What plane is this symmetry seen on? Is it dimers that are symmetrical or can a monomer also be internally symmetrical?


Internal symmetry in this case refers to cases where a part of the protein structure can be superimposed (approximately) on another. It's not a strict mathematical symmetry, more a 'resemblance'

For instance in the 12 transmembrane helix transporters, the first six helices are arranged similarly to the second six, such that if one were to cut the protein in half one would see that the two halves (approximately) superimposed.

Fig 3 of this Nature Micro shows it clearly. http://www.nature.com/articles/nmicrobiol20159 Where the blue helices in 3a could be rotated 180 degrees and then look very similar in arrangment to the yellow helices.


Integral membrane protein

An integral membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane proteins are IMPs, but not all IMPs are transmembrane proteins. [1] IMPs comprise a significant fraction of the proteins encoded in an organism's genome. [2] Proteins that cross the membrane are surrounded by annular lipids, which are defined as lipids that are in direct contact with a membrane protein. Such proteins can only be separated from the membranes by using detergents, nonpolar solvents, or sometimes denaturing agents.


Contents

Asymmetry Edit

The lipid bilayer consists of two layers- an outer leaflet and an inner leaflet. [1] The components of bilayers are distributed unequally between the two surfaces to create asymmetry between the outer and inner surfaces. [2] This asymmetric organization is important for cell functions such as cell signaling. [3] The asymmetry of the biological membrane reflects the different functions of the two leaflets of the membrane. [4] As seen in the fluid membrane model of the phospholipid bilayer, the outer leaflet and inner leaflet of the membrane are asymmetrical in their composition. Certain proteins and lipids rest only on one surface of the membrane and not the other.

• Both the plasma membrane and internal membranes have cytosolic and exoplasmic faces • This orientation is maintained during membrane trafficking – proteins, lipids, glycoconjugates facing the lumen of the ER and Golgi get expressed on the extracellular side of the plasma membrane. In eucaryotic cells, new phospholipids are manufactured by enzymes bound to the part of the endoplasmic reticulum membrane that faces the cytosol. [5] These enzymes, which use free fatty acids as substrates, deposit all newly made phospholipids into the cytosolic half of the bilayer. To enable the membrane as a whole to grow evenly, half of the new phospholipid molecules then have to be transferred to the opposite monolayer. This transfer is catalyzed by enzymes called flippases. In the plasma membrane, flippases transfer specific phospholipids selectively, so that different types become concentrated in each monolayer. [5]

Using selective flippases is not the only way to produce asymmetry in lipid bilayers, however. In particular, a different mechanism operates for glycolipids—the lipids that show the most striking and consistent asymmetric distribution in animal cells. [5]

Lipids Edit

The biological membrane is made up of lipids with hydrophobic tails and hydrophilic heads. [6] The hydrophobic tails are hydrocarbon tails whose length and saturation is important in characterizing the cell. [7] Lipid rafts occur when lipid species and proteins aggregate in domains in the membrane. These help organize membrane components into localized areas that are involved in specific processes, such as signal transduction.

Red blood cells, or erythrocytes, have a unique lipid composition. The bilayer of red blood cells is composed of cholesterol and phospholipids in equal proportions by weight. [7] Erythrocyte membrane plays a crucial role in blood clotting. In the bilayer of red blood cells is phosphatidylserine. [8] This is usually in the cytoplasmic side of the membrane. However, it is flipped to the outer membrane to be used during blood clotting. [8]

Proteins Edit

Phospholipid bilayers contain different proteins. These membrane proteins have various functions and characteristics and catalyze different chemical reactions. Integral proteins span the membranes with different domains on either side. [6] Integral proteins hold strong association with the lipid bilayer and cannot easily become detached. [9] They will dissociate only with chemical treatment that breaks the membrane. Peripheral proteins are unlike integral proteins in that they hold weak interactions with the surface of the bilayer and can easily become dissociated from the membrane. [6] Peripheral proteins are located on only one face of a membrane and create membrane asymmetry.

SOME EXAMPLES OF PLASMA MEMBRANE PROTEINS AND THEIR FUNCTIONS
FUNCTIONAL CLASS PROTEIN EXAMPLE SPECIFIC FUNCTION
Transporters Na+ Pump actively pumps Na+ out of cells and K+ in
Anchors integrins link intracellular actin filaments to extracellular matrix proteins
Receptors platelet-derived growth factor receptor binds extracellular PDGF and, as a consequence, generates intracellular signals that cause the cell to grow and divide
Enzymes adenylyl cyclase catalyzes the production of intracellular signaling molecule cyclic AMP in response to extracellular signals

Oligosaccharides Edit

Oligosaccharides are sugar containing polymers. In the membrane, they can be covalently bound to lipids to form glycolipids or covalently bound to proteins to form glycoproteins. Membranes contain sugar-containing lipid molecules known as glycolipids. In the bilayer, the sugar groups of glycolipids are exposed at the cell surface, where they can form hydrogen bonds. [9] Glycolipids provide the most extreme example of asymmetry in the lipid bilayer. [10] Glycolipids perform a vast number of functions in the biological membrane that are mainly communicative, including cell recognition and cell-cell adhesion. Glycoproteins are integral proteins. [2] They play an important role in the immune response and protection. [11]

The phospholipid bilayer is formed due to the aggregation of membrane lipids in aqueous solutions. [4] Aggregation is caused by the hydrophobic effect, where hydrophobic ends come into contact with each other and are sequestered away from water. [6] This arrangement maximises hydrogen bonding between hydrophilic heads and water while minimising unfavorable contact between hydrophobic tails and water. [10] The increase in available hydrogen bonding increases the entropy of the system, creating a spontaneous process.

Biological molecules are amphiphilic or amphipathic, i.e. are simultaneously hydrophobic and hydrophilic. [6] The phospholipid bilayer contains charged hydrophilic headgroups, which interact with polar water. The layers also contain hydrophobic tails, which meet with the hydrophobic tails of the complementary layer. The hydrophobic tails are usually fatty acids that differ in lengths. [10] The interactions of lipids, especially the hydrophobic tails, determine the lipid bilayer physical properties such as fluidity.

Membranes in cells typically define enclosed spaces or compartments in which cells may maintain a chemical or biochemical environment that differs from the outside. For example, the membrane around peroxisomes shields the rest of the cell from peroxides, chemicals that can be toxic to the cell, and the cell membrane separates a cell from its surrounding medium. Peroxisomes are one form of vacuole found in the cell that contain by-products of chemical reactions within the cell. Most organelles are defined by such membranes, and are called "membrane-bound" organelles.

Selective permeability Edit

Probably the most important feature of a biomembrane is that it is a selectively permeable structure. This means that the size, charge, and other chemical properties of the atoms and molecules attempting to cross it will determine whether they succeed in doing so. Selective permeability is essential for effective separation of a cell or organelle from its surroundings. Biological membranes also have certain mechanical or elastic properties that allow them to change shape and move as required.

Generally, small hydrophobic molecules can readily cross phospholipid bilayers by simple diffusion. [12]

Particles that are required for cellular function but are unable to diffuse freely across a membrane enter through a membrane transport protein or are taken in by means of endocytosis, where the membrane allows for a vacuole to join onto it and push its contents into the cell. Many types of specialized plasma membranes can separate cell from external environment: apical, basolateral, presynaptic and postsynaptic ones, membranes of flagella, cilia, microvillus, filopodia and lamellipodia, the sarcolemma of muscle cells, as well as specialized myelin and dendritic spine membranes of neurons. Plasma membranes can also form different types of "supramembrane" structures such as caveolae, postsynaptic density, podosome, invadopodium, desmosome, hemidesmosome, focal adhesion, and cell junctions. These types of membranes differ in lipid and protein composition.

Distinct types of membranes also create intracellular organelles: endosome smooth and rough endoplasmic reticulum sarcoplasmic reticulum Golgi apparatus lysosome mitochondrion (inner and outer membranes) nucleus (inner and outer membranes) peroxisome vacuole cytoplasmic granules cell vesicles (phagosome, autophagosome, clathrin-coated vesicles, COPI-coated and COPII-coated vesicles) and secretory vesicles (including synaptosome, acrosomes, melanosomes, and chromaffin granules). Different types of biological membranes have diverse lipid and protein compositions. The content of membranes defines their physical and biological properties. Some components of membranes play a key role in medicine, such as the efflux pumps that pump drugs out of a cell.

Fluidity Edit

The hydrophobic core of the phospholipid bilayer is constantly in motion because of rotations around the bonds of lipid tails. [13] Hydrophobic tails of a bilayer bend and lock together. However, because of hydrogen bonding with water, the hydrophilic head groups exhibit less movement as their rotation and mobility are constrained. [13] This results in increasing viscosity of the lipid bilayer closer to the hydrophilic heads. [6]

Below a transition temperature, a lipid bilayer loses fluidity when the highly mobile lipids exhibits less movement becoming a gel-like solid. [14] The transition temperature depends on such components of the lipid bilayer as the hydrocarbon chain length and the saturation of its fatty acids. Temperature-dependence fluidity constitutes an important physiological attribute for bacteria and cold-blooded organisms. These organisms maintain a constant fluidity by modifying membrane lipid fatty acid composition in accordance with differing temperatures. [6]

In animal cells, membrane fluidity is modulated by the inclusion of the sterol cholesterol. This molecule is present in especially large amounts in the plasma membrane, where it constitutes approximately 20% of the lipids in the membrane by weight. Because cholesterol molecules are short and rigid, they fill the spaces between neighboring phospholipid molecules left by the kinks in their unsaturated hydrocarbon tails. In this way, cholesterol tends to stiffen the bilayer, making it more rigid and less permeable. [5]

For all cells, membrane fluidity is important for many reasons. It enables membrane proteins to diffuse rapidly in the plane of the bilayer and to interact with one another, as is crucial, for example, in cell signaling. It permits membrane lipids and proteins to diffuse from sites where they are inserted into the bilayer after their synthesis to other regions of the cell. It allows membranes to fuse with one another and mix their molecules, and it ensures that membrane molecules are distributed evenly between daughter cells when a cell divides. If biological membranes were not fluid, it is hard to imagine how cells could live, grow, and reproduce. [5]


What is internal symmetry in membrane proteins? - Biology

Article Summary:

Cells are the basic unit of life. All cells have a common feature known as outer selective permeable membrane called as cell membrane or plasma membrane. Almost all eukaryotic cells contain more complex and complicated system of internal membranes. These internal membranes give rise to membrane covered various compartments within each cell. Cell membranes are mainly composed of lipids and proteins.

The plasma membrane acts as the boundary between the interior of the cell and also the extra cellular fluid that surrounds each and every cell. The lipids mainly present in the plasma membrane are phospholipids. These phospholipids are amphiphilic with the hydrocarbon tail of the molecule being hydrophilic, where as the polar heads are hydrophilic in nature.
1. Most common phospholipids such as cholesterol and phosphatidyl ethanolamine are present in the plasma membrane.
2. Plasma membrane has got watery surface on both the sides that are both inside and outside of the cell. Therefore the phospholipid present in the cell membrane forms a phospholipid bilayer structure with the hydrophobic tails facing each other.

Even though all membrane proteins are present in the membrane, they are structurally as well as functionally diverse from one another. All the biological membrane has got the same basic phospholipid bilayer structure, which are associated with a set of membrane proteins. This lipid and membrane protein structures enables the plasma membrane to carry out all its biological activities.

Some proteins which are present in the plasma membrane are only bound to the surface of the plasma membrane, where as others have one region masked within the membrane and also domains on one or the both the sides of it.

Mostly, protein domains on the extracellular membrane surface, and also they help in cell signalling mechanism. Protein domains which are formed within the membrane, more specifically which form channels and pores in the membrane help in the transportation of biomolecules across the membranes.
Protein domains which face the cytosolic face of the membrane deal with a variety of biological functions, such as they trigger the intracellular signalling pathways or they also act as cytoskeletal proteins.

Membrane proteins can be classified into two main types of proteins such as integral proteins or in other words as intrinsic and peripheral or extrinsic proteins depending upon the nature of the membrane protein interactions. Most of the biomembrane or plasma membranes or cell membrane contains both types of membrane proteins.

Integral Membrane Proteins:

Integral membrane proteins are also called as intrinsic proteins, as one or more parts of these proteins are embedded in the phospholipid bilayer of the cell membrane. Many of the proteins which are associated with the plasma membrane or cell membrane are tightly bound to it. Integral proteins also contain some residues with hydrophobic side chains that interact with fatty acyl groups of the phospholipids which are present in the membrane. This helps in enabling the anchoring of the proteins strongly into the cell membrane.

Most of the integral proteins span the entire phospholipid bilayer. The transmembrane proteins present in the plasma membrane contain one or more membrane-spanning domains. These domains are of four to several hundred residue long, which also extend into the aqueous medium on either side of the bilayer.

Two types of membrane-spanning domains such as one or more α helices or multiple β strands are found in transmembrane proteins. Proteins that contain seven membrane-spanning α helices form a very important and also major class that includes many cell-surface receptor and also bacteriohodopsin.

Some of the transmembrane proteins span the bilayer cell membrane several times and form a hydrophilic channel through which certain ions and also molecules can enter or leave the cell. For example, all G-protein-coupled receptor like receptors of peptide hormones. All the receptors span the cell membrane or plasma membrane seven times.

Transmembrane protein which form the portions within the lipid bilayer are made up of hydrophobic amino acids. Some portions of the transmembrane protein that are projected out from the phospholipid bilayer are mostly made upon hydrophilic amino acids. Proteins that project into the aqueous surrounding of the cell are usually made up of glycoprotein, which also contains many of the hydrophilic sugar residues that are attached to the part of the polypeptides exposed at the cell surface.

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Membrane proteins represent a large proportion of the proteome, but have characteristics that are problematic for many methods in modern molecular biology (that have often been developed with soluble proteins in mind). For structural studies, low levels of expression and the presence of detergent have been thorns in the flesh of the membrane protein experimentalist. Here we discuss the use of cryo-electron microscopy in breakthrough studies of the structures of membrane proteins. This method can cope with relatively small quantities of sample and with the presence of detergent. Until recently, cryo-electron microscopy could not deliver high-resolution structures of membrane proteins, but recent developments in transmission electron microscope technology and in the image processing of single particles imaged in the microscope have revolutionized the field, allowing high resolution structures to be obtained. Here we focus on the specific issues surrounding the application of cryo-electron microscopy to the study of membrane proteins, especially in the choice of a system to keep the protein soluble.

Cryo-electron microscopy of membrane proteins. Electrons pass through the sample and are focused and imaged in the transmission electron microscope. The sample of membrane proteins is encapsulated in a microscopically thin layer of glassy ice. In most cases, free detergent micelles will be present as well as protein/detergent complexes.


Lens Gap Junctions

E.C. Beyer , V.M. Berthoud , in Encyclopedia of the Eye , 2010

Cataract-Causing Insults and Damage to Lens Connexins

Lens proteins , including connexins, can accumulate a variety of post-translational modifications with aging or in association with cataract formation. Oxidation of methionine has been detected in the bovine orthologs of CX46 and CX50. Deamidation of asparagine121 has been detected in the CX50 ortholog. However, it is not certain that these modifications actually occur in vivo, since both methionine oxidation and deamidation may occur during sample preparation. The effects of most of these modifications on gap junction-mediated intercellular communication are unknown.

One of the most-studied etiologies of cataract formation is oxidative stress, which may be linked to changes in connexins and gap junctions. Several studies have used H2O2 treatment of cultured lens cells or isolated lenses to examine the consequences of oxidative stress. Treatment of chicken lentoid-containing cultures with H2O2 leads to dose- and time-dependent changes in the immunoblot pattern of chicken CX46, suggesting that H2O2 leads to its differential phosphorylation. A cleaved form of this connexin has been observed following treatment with high concentrations of H2O2 this is also associated with cell death. Treatment of a CX43-expressing lens cell line with H2O2 leads to an increase in PKCγ activity, an increase in phosphorylation of CX43 in Ser368 as detected by immunoblotting, a decrease in the number of gap junction plaques, and a decrease in dye coupling. Similar effects have also been observed when rat lenses are treated with H2O2. Thus, several pieces of data suggest that oxidative stress leads to alterations in lens intercellular communication through activation of protein kinases and alterations in connexin phosphorylation, which may contribute to cataract formation.


Acidity can change cell membrane properties

Of all the amazing technologies humans have developed, none has matched the complexity of the fundamental building block of nature: the living cell. And none of the cell's activities would be possible without thin lipid membranes, or bilayers,that separate its parts and regulate their functions.

Changes in the packing of the tails into a hexagonal, rectangular-C, or rectangular-P lattice are observed at various pH levels.

Understanding and controlling bilayers' properties is vital for advances in biology and biotechnology. Now an interdisciplinary team of Northwestern University researchers has determined how to control bilayers' crystallization by altering the acidity of their surroundings.

The research, published September 24 in the Proceedings of the National Academy of Sciences, sheds light on cell function and could enable advances in drug delivery and bio-inspired technology.

"In nature, living things function at a delicate balance: acidity, temperature, all its surroundings must be within specific limits, or they die," said co-author Monica Olvera de la Cruz, Lawyer Taylor Professor of Materials Science and Engineering, Chemistry, and (by courtesy) Chemical and Biological Engineering at Northwestern's McCormick School of Engineering. "When living things can adapt, however, they are more functional. We wanted to find the specific set of conditions under which bilayers, which control so much of the cell, can morph in nature."The research, published September 24 in the Proceedings of the National Academy of Sciences, sheds light on cell function and could enable advances in drug delivery and bio-inspired technology.Understanding and controlling bilayers' properties is vital for advances in biology and biotechnology. Now an interdisciplinary team of Northwestern University researchers has determined how to control bilayers' crystallization by altering the acidity of their surroundings.

By taking advantage of the charge in the molecules' head groups, the Northwestern researchers developed a new way to modify the membrane's physical properties. They began by co-assembling dilysine (+2) and carboxylate (-1) amphiphile molecules of varying tail lengths into bilayer membranes at different pH levels, which changed the effective charge of the heads. Bilayers are made of two layers of amphiphile molecules -- molecules with both water-loving and water-hating properties -- that form a crystalline shell around its contents. Shaped like a lollipop, amphiphile molecules possess a charged, water-loving (hydrophilic) head and a water-repelling (hydrophobic) tail the molecules forming each layer line up tail-to-tail with the heads forming the exterior of the membrane. The density and arrangement of the molecules determine the membrane's porosity, strength, and other properties.

Then, using x-ray scattering technology at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) at Argonne National Laboratory's Advanced Photon Source, the researchers analyzed the resulting crystallization formed by the bilayers' molecules.

(To produce electron microscope images of membrane structures, researchers previously have frozen them, but this process is labor-intensive and changes the structural fidelity, which makes it less relevant for understanding membrane assembly and behavior under physiological conditions as carried out inside the human body.)

The Northwestern researchers found that most molecules did not respond to a change in acidity. But those that possessed a critical tail length -- a measure that correlates to the molecules' level of hydrophylia -- the charge of the molecules' heads changed to the extent that their two-dimensional crystallization morphed from a periodic rectangular-patterned lattice (found in more basic solutions) to a hexagonal lattice (found in more acidic solutions). Shells with a higher symmetry, such as hexagonal, are stronger and less brittle than those with lesser symmetry. The change in pH also altered the bilayers' thickness and the compactness of the molecules.

Changing the density and spacing of molecules within membranes could help researchers control the encapsulation and release efficiency of molecules inside a vesicle.


Science and Biology: The Function of a Cell Membrane

The function of a cell membrane, also referred to as the plasma membrane, is to protect the structures within the cell, give shape to the cell and support its structure.

Structures of Cell Membranes

The cell membrane is composed of a double layer of lipids and proteins. There are three different types of proteins found within a cell membrane: structural protein, transport protein and glycoprotein. These layers of lipids and proteins allow the cell membrane to perform its main function, which is to surround the cell and protect it from the outside environment. A cell membrane is selectively permeable, only allowing certain substances to enter and exit the cell. In some cases, a cell membrane can also control the amount of a certain substance allowed to pass through it.

Function of a Cell Membrane

The cell or plasma membrane is meant to protect the cell from its outside environment, while also giving the cell structure and regulating the materials that enter and leave the cell. This regulation ensures that harmful substances don't enter the cell and that essential substances don't leave the cell. Oxygen can easily pass through the cell membrane, because it is necessary for cellular respiration, which is a primary function of a cell. The byproducts of these functions, such as carbon dioxide, are allowed to exit the cell after cellular respiration takes place. Unlike oxygen, water and carbon dioxide, highly charged ions and larger macromolecules can't pass directly through the cell membrane. Instead, they are allowed to enter the cell via proteins embedded in the membrane. Because the cell membrane is essential in protecting the cell and its structure, a hole or rupture in a cell membrane can cause the cell to stop functioning properly and eventually die.

Another essential function of a cell membrane is communication or cell signaling. The cell membrane's receptor proteins bind to molecules from other areas of the body and communicate with them to send a signal inside the cell, telling the cell to perform a certain function. A cell membrane's receptors can be taken over by harmful viruses, such as the human immunodeficiency virus (HIV), causing an infection.

The overall function of a cell membrane can be compared to the function of a castle's drawbridge and outer wall. Just as a drawbridge and wall protect a castle and ensure only certain individuals enter and exit the castle, the cell's membrane offers protection to the cell and regulates which substances are allowed to enter and exit the cell. Cell signaling is similar to using a lookout tower on a castle wall to communicate with neighboring castles.

Cellular Transport

Cellular transport, one of the main functions of a cell membrane, can occur in multiple ways. The first type of cellular transport is passive osmosis and diffusion. This is when substances, such as water and oxygen, pass easily into the cell directly through the cell membrane. The next type of cellular transport is called transmembrane protein transport, which is when small organic molecules are transported into the cell. Endocytosis is the third type of cellular transport. This kind of transport is similar to the cell "eating" other substances and is characterized by the cell engulfing and then absorbing large molecules or even entire other cells. The last type of cellular transport, exocytosis, occurs when a cell removes or secretes substances.


MEMBRANES

Membrane fluidity -- according to the fluid mosaic model, proteins and lipids diffuse in the membrane.

  • preventing ion flux
  • active transport of ions from side to side of the plasma membrane.
  1. Types of molecules that can cross membranes by diffusion:
    • Water and small lipophilic organic compounds can cross.
    • Large molecules ( e.g. proteins) and charged compounds do not cross.
  2. Direction relative to the concentration gradient: movement is DOWN the concentration gradient ONLY (higher concentration to lower concentration).
  3. Rate of diffusion depends on
    • charge on the molecule -- electric charge prevents movement.
    • size -- smaller molecules move faster than larger molecules.
    • lipid solubility -- more highly lipid-soluble molecules move faster.
    • the concentration gradient -- the greater the concentration difference across the membrane, the faster the diffusion.
  4. Direction relative to the membrane: molecules may cross the membrane in either direction, depending only on the direction of the gradient.
  1. Ion channels exist for Na + , K + and Ca ++ movement. These channels are specific for a given ionic species.
  2. Channels consist of protein, which forms a gate that opens and closes under the control of the membrane potential.
  3. Ion movement through channels is always down the concentration gradient.
  1. A carrier must be able to perform four functions in order to transport a substance.
    • Recognition -- to specifically bind the substance that is to be transported.
    • Translocation -- movement from one side of the membrane to the other.
    • Release -- on the other side of the membrane
    • Recovery -- return of the carrier to its original condition so it can go through another cycle of transport.
  2. Terminology: Carriers are also variously called "porters,""porting systems,""translocases,""transport systems" and "pumps."
  3. Carriers resemble enzymes in some of their properties.
    • They are NOT enzymes, as they do NOT catalyze chemical reactions.
    • They are enzyme-like in the following ways. They are specific. They have dissociation constants for the transported substances which are analogous to Km of enzymes. Transport can be inhibited by specific inhibitors. They exhibit saturation, like enzymes do. Diffusion, in contrast, is not saturable, and its rate increases with increasing concentration.
  4. A general model for transport is that the carrier is a protein which changes conformation during the transport process.
  5. Sometimes carriers move more than one molecule simultaneously. Nomenclature:
    • Uniport: a single molecule moves in one direction.
    • Symport: two molecules move simultaneously in the same direction.
    • Antiport: Two molecules move simultaneously in opposite directions.
  1. The characteristics of a carrier operating by passive mediated transport.
    • Faster than simple diffusion
    • Movement is down the concentration gradient only (like diffusion)
    • No energy input is required -- the necessary energy is supplied by the gradient.
    • The carrier exhibits specificity for the structure of the transported substance saturation kinetics specific inhibitability
  2. Examples of passive mediated transport.
    • Glucose transport in many cells. A uniport system Can be demonstrated by the fact that adding substances with structures that resemble the structure of glucose can inhibit glucose transport specifically. It is specific for glucose. The K m for glucose is 6.2 mM (a value in the neighborhood of the blood concentration of glucose, 5.5 mM) The K m for fructose is 2000 mM The transport process involves attachment of glucose outside the cell. Conformational change of the carrier protein. Release of the glucose inside the cell. There is no need to change K m for glucose, since the glucose concentration in the cell is very low.
    • Chloride-bicarbonate transport in the erythrocyte membrane. This is catalyzed by the band 3 protein seen previously. An antiport system: both ions MUST move in opposite directions simultaneously. The system is reversible, and can work in either direction. Movement is driven by the concentration gradient.
  1. There are two sources of energy for active transport.
    • ATP hydrolysis may be used directly.
    • The energy of the Na + gradient may be used in a symport mechanism. The energy of the Na + going down its gradient drives the movement of the other substance. But since the Na + gradient is maintained by ATP hydrolysis, ATP is the indirect source of energy for this process.
  2. The characteristics of a carrier operating by active transport.
    • Can move substances against (up) a concentration gradient.
    • Requires energy.
    • Is unidirectional
    • The carrier exhibits specificity for the structure of the transported substance saturation kinetics specific inhibitability
  3. How can the substance be released from the carrier into a higher concentration than the concentration at which it bound in the first place?
    • The affinity of the translocase for the substance must decrease, presumably by a conformational change of the translocase.
    • This process may require energy in the form of ATP.
  4. Examples of active mediated transport.
    • Ca ++ transport is a uniport system, using ATP hydrolysis to drive the Ca ++ movement. There are two Ca ++ translocases of importance.
      • In the sarcoplasmic reticulum, important in muscle contraction.
      • A different enzyme with similar activity in the plasma membrane.
    • The Na + -K + pump (or Na + -K + ATPase).
      • An antiport system.
      • Importance: present in the plasma membrane of every cell, where its role is to maintain the Na + and K + gradients.
      • Stoichiometry: 3 Na + are moved out of the cell and 2 K+ are moved in for every ATP hydrolyzed.
      • Specificity: Absolutely specific for Na + , but it can substitute for the K + .
      • The structure of the Na + -K + pump is a tetramer of two types of subunits, alpha 2 beta 2 . The beta-subunit is a glycoprotein, with the carbohydrate on the external surface of the membrane.
      • The Na + -K + ATPase is specifically inhibited by the ouabain, a cardiotonic steroid. Ouabain sensitivity is, in fact, a specific marker for the Na + -K + ATPase.
      • The proposed mechanism of the Na + -K + ATPase shows the role of ATP in effecting the conformational change.
        • Na + attaches on the inside of the cell membrane.
        • The protein conformation changes due to phosphorylation of the protein by ATP, and the affinity of the protein for Na + decreases.
        • Na + leaves.
        • K + from the outside binds.
        • K + dephosphorylates the enzyme.
        • The conformation now returns to the original state.
        • K + now dissociates.
    • Na + linked glucose transport is found in intestinal mucosal cells. It is a symport system glucose is transported against its gradient by Na + flowing down its gradient. Both are transported into the cell from the intestinal lumen. Na + is required one Na + is carried with each glucose. The Na + gradient is essential it is maintained by the Na + -K + ATPase.
    • Na + linked transport of amino acids, also found in intestinal mucosal cells, works similarly. There are at least six enzymes of different specificity that employ this mechanism. Their specificity is as follows. Short neutral amino acids: ala, ser, thr. Long or aromatic neutral amino acids: phe, tyr, met, val, leu, ile. Basic amino acids and cystine: lys, arg, cys-cys. Acidic amino acids: glu, asp Imino acids: pro and hypro Beta-amino acids: beta-alanine, taurine.
  1. There are four types of signals.
    • Nerve transmission
    • Hormone release
    • Muscle contraction
    • Growth stimulation
  2. There are four types of messenger molecules.
    • steroids
    • small organic molecules
    • peptides
    • proteins
  3. The messenger may interact with the cell in either of two ways.
    • Entry into the cell by diffusion through the cell membrane (the steroid hormones do this).
    • Large molecules or charged ones bind to a receptor on the plasma membrane.
  4. The events associated with communication via these molecules may include the following.
    • Primary interaction of the messenger with the cell (binding by a receptor).
    • A secondary event, formation of a second messenger. (this is not always found).
    • The cellular response (some metabolic event).
    • Termination (removal of the second messenger).
  1. Steroids are lipid soluble, and can diffuse through the plasma membrane.
  2. Cells which are sensitive to steroid hormones have specific receptor proteins in the cytosol or nucleus which bind the steroid.
  3. The receptor-hormone complex then somehow causes changes in the cell's metabolism, typically by affecting transcription or translation.
  4. The mechanism of termination is unclear, but involves breakdown of the hormone.
  1. Membrane receptors bind specific messenger molecules on the exterior surface of the cell. Either of two types of response may occur.
    • Direct response: binding to the receptor directly causes the cellular response to the messenger.
    • Second messenger involvement: Binding to the receptor modifies it, leading to production of a second messenger, a molecule that causes the effect.
    • In each case messenger binding induces a conformational change in the receptor protein. Binding of the messenger resembles binding of a substrate to an enzyme in that there is a dissociation constant inhibition (by antagonists) which may be competitive, noncompetitive, etc.
  2. A variety of messengers can bind to various tissues.
    • Various cellular responses may occur, depending on the tissue.
    • Either positive or negative responses may occur, even in the same tissue, depending on the type of receptor.
  3. The response of a cell to a messenger depends on the number of receptors occupied.
    • A typical cell may have about 1000 receptors.
    • Only a small fraction (10%)of the receptors need to be occupied to get a large (50%) response.
    • Receptors may have a dissociation constant of about 10 exp -11 this is the concentration of messenger at which they are 50% saturated. Thus very low concentrations of messengers may give a large response.
  1. The receptor is a complex pentameric protein which forms a channel through the membrane.
  2. Mechanism of action.
      Binding of acetylcholine, a small molecule, at the exterior surface causes the channel to open. (Binding)
  3. Na + and K + flow through the channel, depolarizing the membrane. (Response)
  4. The esterase activity of the receptor then hydrolyses the acetylcholine, releasing acetate and choline, and terminating the effect. (Recovery)
  5. The process can now be repeated.
  1. Definition: This intracellular mediator is called a second messenger .
  2. Effect of second messenger formation: Since a receptor usually forms many molecules of second messenger after being stimulated by one molecule of the original effector, second messenger formation is a means of amplifying the original signal.
  3. The formation and removal of the second messenger can be controlled and modulated.

  1. Structure of cAMP: an internal (cyclic) 3', 5'-phosphodiester of adenylic acid.
  2. The mechanism of action of cAMP is to activate an inactive protein kinase.
    • Animated activation sequence.
    • Since an active protein kinase which acts on many molecules of its substrate is produced, this process is an amplification of the original signal.
    • Since the protein kinase is activated by cAMP it is called protein kinase A.

    The reaction ATP < -> cAMP + PPi is reversible, but subsequent hydrolysis of the PPi

  • G-proteins are a class of proteins that are so named because they can react with GTP. There are G-proteins in addition to the ones under consideration here.
  • G s and G i are so named because they stimulate and inhibit, respectively, adenyl cyclase.
  • Structure: G-proteins are complexes of three different subunits, alpha, beta and gamma. Beta and gamma are similar in the G s and G i proteins. The alpha-subunits are different, and are called alpha s and alpha i , respectively.
  • Mechanism: Receptor-messenger interaction stimulates binding of GTP to the alpha-subunits. The alpha-subunit with its bound GTP then dissociates from the beta-gamma complex. The alpha-subunit with its bound GTP then acts on adenyl cyclase. alpha s -GTP stimulates adenyl cyclase. alpha i -GTP inhibits adenyl cyclase.
  • The alpha-subunit of the G-protein has GTPase activity. After it cleaves the GTP it reassociates with the beta-gamma complex to form the original trimer.
  • cAMP already formed is cleaved by cAMP phosphodiesterase.
  • The hormone gradually and spontaneously dissociates from the receptor.
  1. Animated activation sequence.
  2. IP 3 and DG are synthesized by the enzyme, phospholipase C, which has phosphatidylinositol 4,5-bisphosphate (PIP 2 ) phosphodiesterase activity. PIP 2 is a normal minor component of the inner surface of the plasma membrane.
  3. The phosphodiesterase is controlled by a G-protein in the membrane, which activates the phosphodiesterase.
  4. Mechanism: IP 3 and DG have separate effects.
    • IP 3 releases Ca ++ from the endoplasmic reticulum. The Ca ++ then activates certain intracellular protein kinases.
    • DG activates protein kinase c, a specific protein of the plasma membrane.
    • Note that both IP 3 and DG activate protein kinases, which in turn phosphorylate and affect the activities of other proteins.
  5. Termination of the signal occurs at several levels.
    • IP 3 is hydrolyzed.
    • Ca ++ is returned to the endoplasmic reticulum or pumped out of the cell.
    • The GTPase activity of the G-protein hydrolyses the GTP, terminating the activity of the phospholipase C.
  6. Many systems respond to changes on IP 3 and DG. Be aware of the large number of systems affected.

Structure: The insulin receptor is a tetramer with two kinds of subunits, alpha and beta. Disulfide bridges bind them together.


Watch the video: Was ist Symmetrie? (October 2022).