Cell Membranes I and II PDF

[Cell membranes:] Understand the functions of cell membranes: There are six key functions performed by the cell membrane (CM). - The first function is "compartmentalization". The plasma membrane surrounds several organelles within the cell and this increases the efficiency of many subce...

[Cell membranes:] Understand the functions of cell membranes: There are six key functions performed by the cell membrane (CM). - The first function is "compartmentalization". The plasma membrane surrounds several organelles within the cell and this increases the efficiency of many subcellular processes by concentrating the required components to a confined space within the cell. Compartmentalization in eukaryotic cells is largely about efficiency. Separating the cell into different parts allows for the creation of specific microenvironments within a cell. That way, each organelle can have all the advantages it needs to perform to the best of its ability. Cell membrane compartmentalization helps to create controlled conditions inside an organelle. These microenvironments are tailored to the organelle\'s specific functions and help isolate them from the surrounding cytosol. - A second membrane function involves providing a selectively permeable barrier therefore carefully controlling the movement of substances into and out of the cell. Selective permeability of the CM refers to its ability to differentiate between different types of molecules, only allowing some molecules through while blocking others A selectively permeable barrier prevents unrestricted exchange of molecules but allows communication between compartments. Due to the chemical and structural nature of the phospholipid bilayer (hydrophobic core), only lipid-soluble molecules and some small molecules can pass freely pass through the lipid bilayer. Molecules of oxygen, nitrogen and carbon dioxide pass through the membrane via diffusion. Larger uncharged polar molecules, such as glucose, cannot. Charged molecules, such as ions, are unable to diffuse through a phospholipid bilayer regardless of size; even H^+^ ions cannot cross a lipid bilayer by free diffusion. The bilayer is impermeable to larger polar molecules (e.g., amino acids, ATP) as well. - A third membrane function involves "transporting solutes", which refers to the movement of substances across the cell membrane. Substances can move into and out of cells through the CM. The three main types of movement are diffusion, osmosis and active transport. Cell transport refers to the movement of substances across the cell membrane. In this way, cell membranes help maintain a state of homeostasis within cells (and tissues, organs, and organ systems) so that an organism can stay alive and healthy). A concentration gradient occurs when the concentration of particles is higher in one area than another. It is the process used for particles moving from an area of higher concentration in a solution to an area of lower concentration. In passive transport, particles will diffuse down a concentration gradient, from areas of higher concentration to areas of lower concentration, until they are evenly spaced. Concentration gradients are generated and maintained across biological membranes by ion pump enzymes. Energy is required to produce a gradient, so the gradient is a form of stored energy. During active transport, substances move against the concentration gradient, from an area of low concentration to an area of high concentration. This process is "active" because it requires the use of energy (usually in the form of ATP). It is the opposite of passive transport. In facilitated diffusion, the direction of transport is always down a concentration gradient from one side of the membrane where the substrate concentration is high to the other side of the membrane where the concentration is lower. Facilitated diffusion involves the use of carrier and channel proteins. These membrane transport proteins enable diffusion without requiring additional energy. Channel Proteins Channel proteins form a hydrophilic pore through which charged molecules can pass through, thus avoiding the hydrophobic layer of the membrane. Channel proteins are specific for a given substance. For example, aquaporins are channel proteins that specifically facilitate the transport of water through the plasma membrane. Channel proteins are either always open or gated by some mechanism to control flow. Gated channels remain closed until a particular ion or substance binds to the channel, or some other mechanism occurs. Gated channels are found in the membranes of cells such as muscle cells and nerve cells. Carrier Proteins Carrier proteins bind to a specific substance causing a conformational change in the protein. Conformational change enables movement down the substance's concentration gradient. For this reason, the rate of transport is not dependent on the concentration gradient, but rather on the number of carrier proteins available. Although it is known that proteins change shape when their hydrogen bonds are destabilized, the complete mechanism by which carrier proteins change their conformation is not well understood. - A fourth membrane function involves cell "communication" with other cells through receiving signals. Many of the proteins in the membrane are involved in communication. When these molecules bind with the proteins in the cellular membrane they trigger a change in the protein, which then sends that message into the cell and activates a specific cellular response. Intercellular communication refers to the communication between cells. Membrane vesicle trafficking has an important role in intercellular communications in humans and animals, e.g., in synaptic transmission, hormone secretion via vesicular exocytosis. Cells have proteins called receptors that bind to signaling molecules and initiate a physiological response. Cell-surface receptors. This type of receptor spans the plasma membrane and performs signal transduction, converting an extracellular signal into an intracellular signal. The 5 types of receptors that include: - Chemoreceptors detect the presence of chemicals - Thermoreceptors detect changes in temperature - Mechanoreceptors detect mechanical forces - Photoreceptors detect light during vision - More specific examples of sensory receptors are baroreceptors, proprioceptors, hygroreceptors, and osmoreceptors. - A fifth membrane function involves providing a "scaffold" structure for biochemical activities. Membrane proteins are important for transporting substances across the cell membrane. They can also function as enzymes or receptors. As a scaffold for biochemical activities, membranes provide the cell with extensive framework within which components can be ordered for effective interactions. Membranes are the site of many biochemical reactions because the enzymes (E) involved are embedded in the membrane structure. Chemical reactions happen quicker if the proteins/enzymes needed are closely associated with each other and in the correct order along a pathway. CM compartmentalizes enzymes & substrates closer to each other to [increase] their collisions & increased chance of successful collision between enzymes active site & substrate (e.g., energy transduction via mitochondrial & cytoplasmic membranes) Membrane-bound organelles offer several advantages to eukaryotic cells. First, cells can concentrate and isolate enzymes and reactants in a smaller volume, thereby increasing the rate and efficiency of chemical reactions - A sixth membrane function involves providing a "scaffold" structure to maintain cellular shape and strength. The plasma membrane provides structural support to the cell. It tethers the cytoskeleton, which is a network of protein filaments (actin thin filaments, intermediate filaments and microtubules) inside the cell that hold all the parts of the cell in place. This helps cells to move (e.g. crawl, locomotion, swim) and give the cell its shape The cell membrane supports cytoskeleton (actin, microtubule & intermediate filaments) by providing attachment sites. Cytoskeleton interacts with extracellular matrix via transmembrane molecules providing cell shape & strength The cytoplasm of all eukaryotic cells contains a three-dimensional network of protein fibers which has been termed the cytoskeleton. The roles of the cytoskeleton include: - Transport around the cell, maintain shape - Provides support - Movement of vesicles and other objects - Pull chromosomes apart during mitosis - Microtubules (create highways for protein and pull chromosomes during mitosis), intermediate filaments (shape of cell), microfilaments (create highways for vesicles). [Basic aspects of the cell membrane:] The cell membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane encloses the cell, defines its boundaries, and maintains the essential differences between the cytosol and the extracellular environment. The membrane is a sheet-like bilayer composed of amphipathic (both polar & non-polar parts) lipids. CM are "dynamic" (i.e. constantly moving = not "static") fluid structures and most of the molecules move about in the plane of the membrane. Since lipids are dynamic and can regularly move between the layers of the and this is the fluid-mosaic model for the phospholipid bilayer. Lipids are arranged in a continuous double layer about 5nm thick. The lipid bilayer provides the basic structure of the membrane and serves as a selectively permeable barrier allowing lipid-soluble but not water-soluble substances to diffuse. The fluid mosaic model of the cell membrane is how scientists describe what the cell membrane appears structurally and functionally because it is composed of different molecules that are distributed across the membrane. The movement of the mosaic of molecules (i.e. including phospholipids, cholesterol, proteins, and carbohydrates) gives the membrane a fluid character, and makes it impossible to form a completely impenetrable barrier. The components of bilayers are distributed unequally between the two surfaces to create asymmetry between the outer and inner surfaces. This asymmetric organization is important for cell functions such as cell signaling. The asymmetry of the biological membrane reflects the different functions of the two leaflets of the membrane. Certain proteins and lipids rest only on one surface of the membrane and not the other. The hydrophobic core of the phospholipid bilayer is constantly in motion because of rotations around the bonds of lipid tails. 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. This results in increasing viscosity of the lipid bilayer closer to the hydrophilic heads. [Basic lipid structure:] lodish 6th 2-13 crop In water, lipid molecules spontaneously align --- with their heads **facing** outward and their tails lining up in the **bilayer\'s** interior. Thus, the hydrophilic heads of the glycerophospholipids in a cell\'s plasma **membrane face** both the water-based **cytoplasm** and the exterior of the cell. **Phospholipids** of the composition present in cells spontaneously form symmetric **sheetlike** phospholipid **bilayers**, which are two molecules thick. The **hydrocarbon** side chains in each **leaflet** form a hydrophobic **core** that is 3 -- 4 nm thick in most bio membranes. The various phospholipids differ in the charge carried by the **polar head groups** at neutral pH: some phosphoglycerides (e.g., phosphatidylcholine and phosphatidylethanolamine) have no net electric **charge**; others (e.g., phosphatidylglycerol and phosphatidylserine) have a net negative charge. Nonetheless, the **polar** **head** groups in all phospholipids can pack together into the characteristic **bilayer** structure. Sphingomyelins are similar in shape to phosphoglycerides and can form mixed bilayers with them. Phospholipids **structure (saturated** or **unsaturated)** contributes to **fluidity:** **Saturated tails: single** bonds between carbon atoms **= straight-shaped** tails & packed **tightly** (**↓distance** between PL) **Unsaturated tails: double** bonds between **carbon** atoms **=** **kinked-shaped** & **not** packed **tightly** (**↑distance** between PLs) Fatty acids tails of phospholipids can be either saturated or unsaturated. Saturated fatty acids have single bonds between the hydrocarbon backbone and are saturated with the maximum number of hydrogens. These saturated tails are straight and can, therefore, pack together tightly. In contrast, unsaturated fatty acid tails contain double bonds between carbon atoms, giving them a kinked shape and preventing tight packing. Increasing the relative proportion of phospholipids with unsaturated tails results in a more fluid membrane. Organisms like bacteria and yeasts that experience environmental temperature fluctuations can adjust the fatty acid content of their membranes to maintain a relatively constant fluidity.  Fatty acids tails of phospholipids can be either saturated or unsaturated. Saturated fatty acids have single bonds between the hydrocarbon backbone and are saturated with the maximum number of hydrogens. These saturated tails are straight and can, therefore, pack together tightly. In contrast, unsaturated fatty acid tails contain double bonds between carbon atoms, giving them a kinked shape and preventing tight packing. Increasing the relative proportion of phospholipids with unsaturated tails results in a more fluid membrane. Organisms like bacteria and yeasts that experience environmental temperature fluctuations can adjust the fatty acid content of their membranes to maintain a relatively constant fluidity. This means there is a lot more space when you have unsaturated phospholipids. [Interaction with cholesterol:] Cholesterol interacts with phospholipid heads immobilizing hydrocarbon chain decreasing ability of polar molecules to cross the cell membrane. Cholesterol prevents phospholipids from packing tightly, prevents membrane freezing. Cholesterol is "structural buffer", preventing lower temperatures from inhibiting fluidity & preventing increasing temperatures from increasing fluidity too much. In cell membranes, cholesterol can interact with heads of phospholipids, partly immobilizing the proximal part of the hydrocarbon chain. This interaction decreases the ability of polar molecules to cross the membrane. Cholesterol also prevents the phospholipids from packing together tightly, thereby preventing the likelihood of membrane freezing. Likewise, cholesterol acts as a structural buffer when temperatures get to warm, limiting excessive fluidity. Cholesterol is also proposed to have a role in the organization of membrane lipids and proteins into functional groups called lipid rafts. These groups of proteins, phospholipids, and cholesterol are thought to compartmentalize regions of the membrane, positioning molecules with similar roles near one another. However, the specific structure and function of these membrane patches are unclear and an active area of research. [Covalent bonds in cell membrane:] The lipid bilayers are stabilized by the full array of forces that mediate molecular interactions in biological systems. Cooperative non-covalent interactions hold the bilayer together: Hydrophobic interactions - ensure hydrocarbon tails sequestered away from aqueous surroundings (i.e., hydrophobic core). Hydrophobic interactions are the major driving force for the formation of lipid bilayers. Note: hydrophobic interactions also play a dominant role in the folding of proteins and in the stacking of bases in nucleic acids. Water molecules are released from the hydrocarbon tails of membrane lipids as these tails become sequestered in the nonpolar interior of the bilayer. hydrophobic effect is a noncovalent interaction in which hydrophobic molecules aggregate to minimize contact with water in an aqueous environment. Consequently, the hydrophobic regions of a polypeptide become buried within the structure during protein folding. Van der Waals forces - attraction between hydrocarbon tails favors close packing. These forces are driven by temporary attractions between electron-rich and electron-poor regions of two or more atoms (or molecules) that are near each other. These interactions can contribute to the three-dimensional structures of proteins essential for their function Electrostatic & hydrogen bonding - interactions between polar headgroups & water molecules keep bilayers together. Lipid bilayers are held together by many reinforcing, noncovalent interactions (predominantly hydrophobic), they are cooperative structures. These hydrophobic interactions have three significant biological consequences: (1) lipid bilayers have an inherent tendency to be extensive; (2) lipid bilayers will tend to close on themselves so that there are no edges with exposed hydrocarbon chains, and so they form compartments; and (3) lipid bilayers are self-sealing because a hole in a bilayer is energetically unfavorable. The cell membrane consists of three classes of amphipathic lipids: phospholipids, glycolipids, and sterols. The amount of each depends upon the type of cell, but in most cases phospholipids are the most abundant, often contributing for over 50% of all lipids in plasma membranes. Integral membrane proteins, also called intrinsic proteins, have one or more segments that are embedded in the phospholipid bilayer. Most integral proteins contain residues with hydrophobic side chains that interact with fatty acyl groups of the membrane phospholipids, thus anchoring the protein to the membrane. Membrane proteins can serve a variety of key functions: - **Junctions** -- Serve to **connect** and join two **cells** **together**. - **Enzymes** -- Fixing to membranes **localizes** **metabolic** **pathways**. - **Transport** -- Responsible for **facilitated** **diffusion** and active transport. - **Recognition** -- May function as **markers** for cellular **identification**. **Membrane proteins** may extend partway into the plasma **membrane**, cross the **membrane** entirely, or be loosely attached to its inside or outside face. Carbohydrate groups are present only on the outer surface of the plasma **membrane** and are attached to **proteins**, forming **glycoproteins**, or **lipids**, forming **glycolipids**. They form hydrogen bonds with the water molecules surrounding the **cell** and thus help to stabilize **membrane** structure. **Cholesterol** constitutes up to 30% of the CM (most abundant substance), has capacity to fit in spaces in the middle of the phospholipids and prevents diffusion across the CM of water-soluble molecules, thus reducing permeability of the CM.  Glycocalyx is the collection of glycoproteins on the outside of the cell membrane and these act as receptors, immune reactions, attachment to neighboring cells [Determine how metabolically active a cell is based on contents:] Based on composition of the cell membrane we can tell how stable and how metabolically active it is. The principal components of a PM are **lipids** (phospholipids and cholesterol), **proteins**, and **carbohydrates**. The **proportions** of proteins, lipids, and carbohydrates in PM vary with organism and cell type, but for a typical human cell, **proteins** account for about **50**% of the composition by mass, **lipids** (of all types) account for about **40%** of the composition by mass, and **carbohydrates** account for the remaining **10**% of the composition by mass. However, the concentration of proteins and lipids varies with **different** cell **membranes**. M**yelin** contains only **18%** **protein** and **76%** **lipid and 3% carbohydrate**, and as such, the CM has **high** **stability** but **low metabolic** activity.  The **mitochondrial** inner **membrane** contains **76% protein** and only **24% lipid** and is therefore much more metabolically active. **High** metabolic **rates** require a **high** enzyme **density**. The **inner** membrane of **mitochondria** contains an unusually high fraction (\~76%) of **protein**, reflecting the **abundance** of **protein** complexes involved in electron **transport** and oxidative **phosphorylation**. **Generally, the greater amount of protein (i.e., enzymes) is indicative of high metabolic activity.** There are no carbohydrates, since these are only found on the exterior of the outer CM and used for signaling. **Polysaccharides (carbohydrates) are absent from internal membranes.** **High metabolic activity- lots of protein and small amounts of lipids** In summary, membranes that are **rich in proteins** are typically **more metabolically active** because proteins are directly involved in the enzymatic and transport functions that drive metabolism. Conversely, membranes with higher lipid content are less involved in metabolic activity. [Red blood cells:] A close-up of a chart Description automatically generated The plasma membrane of human red **blood** cells is **43% lipid**, **49% protein** and **8% carbohydrate**, and represents a stable and metabolically active (due to high percentage of proteins) membrane. For example, the RBC needs to live for 120 days and during its time in the circulatory system, it is being deformed to fit through micro-capillaries and reformed when in large blood vessels. The membrane needs to be "stable" (i.e., strong and have high compressibility due to a high percentage of cholesterol molecules) to withstand the pressures of deformation/reformation. The metabolically active nature of the RBC PM denotes its job to transport oxygen to the body\'s tissues in exchange for carbon dioxide, which is carried to and eliminated by the lungs. Red blood cell membranes are 1.5--2.0-times richer in cholesterol compared with any other cell in the body, and approximately 40% of their weight is composed of lipids. [General rules for chemical diversity of membranes:] - Higher the percentage of lipids, the more stable the cell membrane (CM). - Greater amounts of protein (enzymes) indicate high metabolic activity. - Polysaccharides (carbohydrates) are absent from internal membranes. - Cholesterols reduces permeability of CM & increases compressibility. Cellular membranes are formed from a chemically diverse set of lipids present in various amounts and proportions. A high lipid diversity is universal in eukaryotes and is seen from the scale of a membrane leaflet to that of a whole organism, highlighting its importance and suggesting that membrane lipids fulfil many functions. Indeed, alterations of membrane lipid homeostasis are linked to various diseases. While many of their functions remain unknown, interdisciplinary approaches have begun to reveal novel functions of lipids and their interactions. We are beginning to understand why even small changes in lipid structures and in composition can have profound effects on crucial biological functions. Cholesterol modulates the bilayer structure of biological membranes in multiple ways. It changes the fluidity, thickness, compressibility, water penetration and intrinsic curvature of lipid bilayers. Temperature affects the fluidity of the cell membrane by altering the physical state of the phospholipids that make up the bilayer. At high temperatures, the phospholipids become more fluid and flexible, allowing more movement of molecules and proteins within and across the membrane. This can increase the permeability of the membrane and potentially allow harmful substances to enter the cell. At low temperatures, the phospholipids become more rigid and packed, reducing the movement and fluidity of the membrane. This can decrease the permeability of the membrane and restrict the entry of essential molecules such as oxygen and glucose into the cell. Therefore, cells need to maintain an optimal temperature range to ensure proper membrane function and stability. Role of cholesterol Low temp- keep membrane fluids High temp- pulls them together and prevents membrane being leaky Cholesterol is a major determinant of bilayer fluidity, although its effect depends on the composition of a membrane [Lipid Bilayer mobility: ] Fluid-Mosaic Model tenet is that components of bilayers free to move Lipids undergo rapid lateral diffusion Lipids rotate about their axis perpendicular to plane of bilayer Phospholipids have transverse diffusion ("flip flop"); rare Lateral movement provides the membrane with a fluidity One of the tenets of the Fluid-Mosaic membrane model is that the components of the bilayers are free to move. Using a phospholipid as an example, the first type of movement is rotational. Here the phospholipid rotates on its axis to interact with its immediate neighbors. The second type of movement is lateral, where the phospholipid moves around in one leaflet. Finally, it is possible for phospholipids to move between the bilayers in transverse movement, in a "flip-flop" manner. Lateral movement is what provides the membrane with a fluid structure. Lipids were found to move by "hop diffusion". There is constant movement of phospholipids whilst proteins do not flip-flop. [Membrane asymmetry:] Scramblases ensure both monolayers remain equally populated (fill gaps in inner & outer lipid bilayer). Flippases move phospholipids from the outer bilayer to the inner bilayer. To maintain the charge gradient across the membrane, flippases predominantly transport phosphatidylserine and to a lesser extent phosphatidylethanolamine. Floppases move phospholipids in the opposite direction, particularly the choline derived phospholipids phospatidylcholine and sphingomyelin. Floppases also mediate cholesterol transport from the intracellular monolayer to the extracellular monolayer. These catalyzed movements are typically dependent on ATP hydrolysis. A third class of protein are the scramblases, which exchange phospholipids between the two leaflets in a calcium activated, ATP-independent process. In the case of membrane proteins, they can undergo rotational and lateral movement. However, there is no transverse movement of proteins between the leaflets. Intrinsic membrane proteins are tightly embedded in the hydrophobic core, whereas extrinsic membrane proteins associate with their required leaflet. The energy requirements to move either type of membrane protein across the bilayer would be excessive. Phospholipids with choline headgroup (sphingomyelin & phosphatidyl choline) predominantly in exoplasmic bilayer whilst phospholipids with terminal amino group (serine & ethanolamine, inositol) found in cytoplasmic bilayer. Cholesterol found in both leaflets & most abundant (25-30%) of lipids in cell membrane. Lipid asymmetry not absolute (lipids present on both sides of bilayer in different amounts) The outer monolayer contained phospholipids with choline in their polar head group such as phosphatidylcholine and sphingomyelin. Conversely, inner monolayer phospholipids were those with a terminal primary amino group, namely phospatidylserine, and phosphatidylethanolamine. **Cholesterol** is distributed **evenly** throughout the **two** monolayers. Altogether, lipids account for about half the mass of cell membranes. Cholesterol molecules, although less abundant than glycerophospholipids, account for about **20 percent** of the lipids in animal cell plasma membranes. However, cholesterol is not present in bacterial membranes or mitochondrial membranes.Although most **phospholipids** are **neutral** at physiologic pH, **phosphatidylserine** and **phosphatidylinositol** have a **net negative charge** at physiologic pH. Being present predominately in the **inner** leaflet, these two lipids generate a significant difference in **charge** between the **two leaflets** of the lipid bilayer. The cholesterol molecules enhance the permeability-barrier properties of the lipid bilayer. They orient themselves in the bilayer with their hydroxyl groups close to the polar head groups of the phospholipid molecules. In this position, their rigid, platelike steroid rings interact with---and partly immobilize---those regions of the hydrocarbon chains closest to the polar head groups. By decreasing the mobility of the first few CH~2~ groups of the hydrocarbon chains of the phospholipid molecules, cholesterol makes the lipid bilayer less deformable in this region and thereby decreases the permeability of the bilayer to small water-soluble molecules. Although cholesterol tends to make lipid bilayers less fluid, at the high concentrations found in most eucaryotic plasma membranes, it also prevents the hydrocarbon chains from coming together and crystallizing. In this way, it inhibits possible phase transitions.