Membrane Structure and Function (Biochemistry Trans 1) PDF

BIOCHEMISTRY TRANS 1 LE MEMBRANE: STRUCTURE AND FUNCTION DR. EJ BALMORES | 08/27/2024 | Version 1...

BIOCHEMISTRY TRANS 1 LE MEMBRANE: STRUCTURE AND FUNCTION DR. EJ BALMORES | 08/27/2024 | Version 1 1 OUTLINE I. CELL MEMBRANE C. MOVEMENT OF LARGE A. STRUCTURE & MOLECULES FUNCTION c.1. Endocytosis A.1. LIPIDS c.2. Exocytosis a. Phospholipids II. GENETIC MUTATIONS b. Glycosphingolipids III. References c. Sterols IV. Formative quiz A.2. PROTEINS A.3. CARBOHYDRATES II. TRANSPORT MECHANISM A. PASSIVE TRANSPORT B. ACTIVE TRANSPORT Must Lecturer Book Previous Youtube Fig. 1. Fluid Mosaic Model Know Trans Video ❗ 💬 📖 📋 🔺 SUMMARY OF ABBREVIATIONS MAJOR LIPIDS IN MAMMALIAN MEMBRANE GSL Glycosphingolipids PHOSPHOLIPIDS LEARNING OBJECTIVES → Phospholipids consist of several parts ✔ Know that biological membranes are mainly composed of a lipid ▪ Alcohol + Phosphodiester bridge + Diacylglycerol bilayer and associated proteins and glycoproteins. The major (DAG) or Spingosine lipids are phospholipids, cholesterol, and glycosphingolipids. ▪ There is an alcohol portion ✔ Appreciate that membranes are asymmetric, dynamic structures ▪ The alcohol is glycerol (black part in the image) containing a mixture of integral and peripheral proteins. ▪ Connected to the alcohol via a phosphodiester ✔ Know the fluid mosaic model of membrane structure and that it is bridge is widely accepted, with lipid rafts, caveolae, and tight junctions diacylglycerol or sphingosine. being specialized features. ▪ The important parts are: an alcohol, phosphodiester ✔ Understand the concepts of passive diffusion, facilitated bridge, and diacylglycerol or sphingosine depending on the diffusion, active transport, endocytosis, and exocytosis. specific type of phospholipids. ✔ Recognize that transporters, ion channels, the Na+ − K+- FIG.2. PHOSPHOLIPID STRUCTURE ATPase, receptors, and gap junctions are important participants in membrane function. ✔ Know that a variety of disorders result from abnormalities of membrane structure and function, including familial hypercholesterolemia, cystic fibrosis, hereditary spherocytosis, and many others. I. CELL MEMBRANE A. STRUCTURE AND FUNCTION GLYCOSPHINGOLIPIDS → also known as the PLASMA MEMBRANE ▪ are sugar-containing lipids built on a backbone of ceramide ▪ Location: plasma membranes of cells, displaying their → form closed compartments around the cytoplasm to define sugar components to the exterior of the cell. cell boundaries in eukaryotic cells. STEROLS → divide the internal space into discrete compartments to ▪ most common sterol in the membranes of animal cells segregate processes and components. is cholesterol. ▪ Location: majority of cholesterol resides within plasma → has selective permeabilities and acts as a barrier, thereby membranes, but smaller amounts are found within maintaining differences in composition between the inside and mitochondrial, Golgi complex, and nuclear outside of the cell. membranes. → composed primarily of lipids and proteins with a lipid bilayer (hydrophilic end and hydrophobic end) CHOLESTEROL -basic lipid bilayer is composed of phospholipid molecules acts as a buffer to modify the fluidity of membranes. -phosphate end: hydrophilic fluidity of a membrane significantly affects its functions. -fatty acid portion: hydrophobic As membrane fluidity increases, so does its permeability ✔The current model of the cell membrane is the Fluid Mosaic to water and other small hydrophilic molecules. Model o proposed in 1972 by Singer and Nicolson o protein “icebergs” floating in a sea of (predominantly) fluid phospholipid molecules LE 1 TG 1 | Gumpal, Hampuy, Mallari | | PAGE 1 of 6 TRANS 1 BIOCHEMISTRY| LE1 Membrane: Structure and Function | Dr. EJ Balmores MEMBRANE LIPIDS ARE AMPHIPATHIC c. CONCENTRATION DEPENDENT Whenever a substance exists in greater concentration on one side → contain both hydrophobic and hydrophilic regions and are of a semipermeable membrane, such as the cell membranes, any therefore termed amphipathic. substance that can move down its concentration gradient across → the polar head groups of the phospholipids and the hydroxyl the membrane will do so group of cholesterol interface with the aqueous environment. Saturated fatty acids o form relatively straight tails Unsaturated fatty acids o generally, exist in the cis form in membranes, form “kinked” tails trans fatty acids-the membrane lipids become less tightly packed and the membrane more fluid MEMBRANE PROTEINS ASSOCIATED WITH LIPID BILAYER Integral Proteins -are usually globular and require the use of detergents for their solubilization. -are firmly embedded within the lipid bilayer and are removable only by agents such as detergents or organic solvents that overcome hydrophobic interactions Additional: MEMBRANE PROTEINS CAN ALSO ACT AS SURFACE Peripheral proteins RECEPTORS FOR SIGNAL TRANSDUCTION TO OCCUR (next -associated with the membrane through electrostatic interactions topic) and hydrogen bonding with hydrophilic domains of integral proteins 📖 LIPID RAFTS, CAVEOLAE AND TIGHT JUNCTIONS and with the charged head groups of membrane lipids. are specialized structures whose biochemical natures have been -found on either the extracellular/ intracellular surface. investigated in some detail and are involved in the lateral Fig. 2. Membrane Proteins compartmentalization of molecules at the cell surface. → LIPID RAFTS ▪ specialized areas of the exoplasmic (outer) leaflet of the lipid bilayer enriched in cholesterol, sphingolipids and certain proteins. ▪ hypothesized to be involved in signal transduction and other processes. ❗Proteins allow for transport to be: a. SELECTIVE- permits passageway of specific molecules Fig. 6 Lipid rafts- yellow colored → CAVEOLAE May derive from lipid rafts. many, but not all contain the protein caveolin-1 observable by electron microscopy as flask-shaped indentations of the cell membrane into the cytosol. Fig. 3. movement of proteins b. BI-DIRECTIONAL- movement of molecules may be intracellular/extracellular Fig. 7. Caveolae ➔ TIGHT JUNCTIONS - structures found in the surface membranes. Fig 4. movement of proteins -are intercellular adhesion complexes in epithelia and endothelia that control paracellular permeability. -Location: below the apical surfaces of epithelial cells and prevent the diffusion of macromolecules between cells BIOCHEMISTRY MEMBRANE: STRUCTURE AND FUNCTION PAGE 2 of 6 BIOCHEMISTRY| LE1 Membrane: Structure and Function | Dr. EJ Balmores II. CELL MEMBRANE TRANSPORT MECHANISM A. DIFFUSION B. ACTIVE TRANSPORT OSMOSIS - net movement of water caused by a concentration difference - process by which the molecules of a solvent pass from a solution of low concentration to a solution of high concentration through a semipermeable membrane → Three different types of solution ○ Isotonic has the same concentration of solutes both inside and outside the cell ○ Hypertonic Fig 9. Transport mechanisms has a higher solute concentration ACTIVE TRANSPORT compared to the intracellular solute ▪ is vectorial movement of a solute against a concentration concentration gradient, thus requiring ATP. causes shrinkage ▪ The major ATP driven pumps are classified as P ○ Hypotonic (Phosphorylated), F (energy factors), V (vacuolar), and ABC has a lower solute concentration Transporters. compared to the intracellular solute concentration Table 1. Major types of ATP Driven Active Transporters causes swelling Type Example with Subcellular Location P-type Ca2+, ATPase (SR); Na+, K; ATPase (PM) F-type mt ATP synthase of oxidative phsophorylation V-type The ATPase that pumps protons into lysosomes SIMPLE DIFFUSION and synaptic vesicles → the passive flow of a solute from a higher to lower concentration ABC CTFR Protein (PM); MDR-1 protein (PM) due to random thermal movement. Transporter 3 FACTORS THAT LIMIT SIMPLE DIFFUSION 1. The thermal agitation of that specific molecule CROSS MEMBRANE MOVEMENT OF LARGE MOLECULES 2. The concentration gradient across the membrane 3. The solubility of that solute in the membrane bilayer. ENDOCYTOSIS → PASSIVE DIFFUSION → process by which cells take up large molecules. ▪ does not require energy → involves ingestion of parts of plasma membrane. → FACILITATED DIFFUSION → also provides a mechanism for regulating the content of certain ▪ a passive transport of a solute from a higher to lower membrane components (e.g. hormones) concentration mediated by a specific protein carrier. ▪ Most endocytic vesicles fuse to primary lysosomes to form ▪ “ping-pong” mechanism - the carrier protein exists in 2 secondary lysosomes which contain hydrolytic enzymes. principal conformations. ▪ Digested contents are digested to yield Amino Acids, simple ▪ “ping” state- exposed to high concentrations of solute, and sugars and nucleotides. − molecules are bound to a specific site of carrier protein. Endocytosis require: ▪ “pong” state- binding induces conformational change that o Energy- usually from hydrolysis of ATP exposes the carrier to a lower concentration of solute. o Calcium ion and o Contractile filaments (microfilaments) - Two general types of Endocytosis: a. PHAGOCYTOSIS -involves ingestion of large particles such as viruses, bacteria, cells or debris. -occurs only in specialized cells such as MACROPHAGES and GRANULOCYTES. b. PINOCYTOSIS “cell-drinking” -the cellular uptake of extracellular fluid and fluid contents into small vesicles. 2 TYPES OF PINOCYTOSIS → ABSORPTIVE PINOCYTOSIS - receptor-mediated endocytosis - the vesicles are derived from invaginations (pits) that are coated on the cytoplasmic side with a filamentous material (coated pits) - Clathrin-filamentous protein. - Dynamin-protein that is necessary for the pinching off of clathrin-coated vesicles from the surface. Fig 8. The “ping-pong” model → FLUID-PHASE PINOCYTOSIS -non-selective -uptake of a solute by formation of small vesicles BIOCHEMISTRY MEMBRANE: STRUCTURE AND FUNCTION PAGE 3 of 6 BIOCHEMISTRY| LE1 Membrane: Structure and Function | Dr. EJ Balmores → Ligand gated channels a specific molecule binds to a receptor and opens the channel. → Mechanically-gated Fig. 10 2 types of movement of large molecules channels respond to mechanical stimuli RECEPTOR-MEDIATED ENDOCYTOSIS → Voltage-gated channels Requires a specific receptor protein located in the cell open (closes) in response to changes in membrane. membrane potential Cell receptors interact with the molecule to be transported into Na+ channel is an example of voltage-gated. the cell through a ligand – a molecule that binds specifically to the receptor. Highly specific (eg. Some viruses, i.e HIV, enter the cell through receptor-mediated endocytosis. GAP JUNCTIONS Mutations involved usually block the entrance of substances Are structures that permit direct transfer of small molecules from meant to be transported by this process. one cell to its neighbor. Composed of family of proteins called connexins that form a bihexagonal structure consisting of 12 such proteins. EXOCYTOSIS Allows direct flow from one cell to another. → the process wherein the components synthesized in the ER and Golgi are carried in vesicles that fuse with the plasma membrane. → Molecules released of this mode have at least 3 fates: 1. they are membrane proteins and remain associated with the cell surface 2. they can become part of the extracellular matrix 3. They can enter the extracellular matrix and signal other cells. TRANSPORT SYSTEM 1. TRANSPORTERS Fig. 11.GAP JUNCTIONS: CONNEXIN -Also known as carriers or permeases. Active transporters are often called pumps. EXTRACELLULAR VESICLES (EXOSOMES) -Can be classified with regard to the direction of movement and a class of small, heterogeneous, secreted vesicles whether one or more unique molecules are moved. implicated as a new and important mediator of cell-cell A. Uniport system communication -moves one type of molecule bidirectionally enclosed by a lipid bilayer B. Cotransport system generated by at least two (2) distinct mechanisms: -the transfer of one solute depends upon the stoichiometric Microvesicles simultaneous or sequential transfer of another solute. - generated by budding from the plasma C. Symport membrane of a source cell -moves 2 solutes in the same direction. Exosomes -eg. Proton sugar transporter in bacteria - generated from the multivesicular body D. Antiport (MVB) -move 2 molecules in opposite directions. ○ a component of the - eg. Na2+ in and Ca2+ out endocytic membrane ION CHANNELS trafficking system - secreted from the source cell on fusion Basically made up of transmembrane subunits that come of the MVB with the plasma membrane. together to form a central pore through which ions pass selectively. Ion channels are open transiently and thus are “gated”. Gates can be controlled by opening or closing. BIOCHEMISTRY MEMBRANE: STRUCTURE AND FUNCTION PAGE 4 of 6 BIOCHEMISTRY| LE1 Membrane: Structure and Function | Dr. EJ Balmores MUTATIONS AFFECTING MEMBRANE PROTEINS CAUSE DISEASES Fig. 13. Wilson disease defective gene ATP7B. ATP7B facilitates membrane transport of copper within hepatocytes. Fig. 14. Long QT syndrome. It is caused by variants in the CYSTIC FIBROSIS KCNH2 gene (also known as hERG) on chromosome 7 which is a recessive genetic disorder prevalent among whites in encodes the potassium channel that carries the rapid inward North America and certain parts of northern Europe. rectifier current IKr. characterized by chronic bacterial infections of the airways and sinuses fat maldigestion due to pancreatic exocrine insufficiency causes infertility in males due to abnormal development of the vas deferens ↑ levels of chloride in sweat (>60 mmol/L) due to mutations in the gene encoding cystic fibrosis transmembrane regulator protein (CFTR) a cyclic AMP-regulated Cl transporter Fig 15. FGFR3 MUTATION- ACHONDROPLASIA Fig 12. Cystic Fibrosis defective gene BIOCHEMISTRY MEMBRANE: STRUCTURE AND FUNCTION PAGE 5 of 6 BIOCHEMISTRY| LE1 Membrane: Structure and Function | Dr. EJ Balmores V. REFERENCES 1. HARPER’s Illustrated Biochemistry 32nd ed. 2. LEHNINGER’S principle of biochemistry 8th ed. Fig. 16. PIG-A gene mutation VI. FORMATIVE QUIZ Question & Choices Answer & Rationale 1. Which of the following is true about the Fluid Mosaic Model? A. proposed in 1972 by Singer and Nicolson B. protein “icebergs” floating in a sea of C (predominantly) fluid phospholipid molecules Imagine the cell membrane proteins as floating icebergs C. Both A and B and the phospholipid molecules as the water D. None of the above surrounding the icebergs. 2. Defective in Cystic fibrosis In cystic fibrosis (CF), an imbalance in ion transport due A. Receptor to an absence of chloride ion secretion, caused by B. Gap junctions C mutations in the cystic fibrosis transmembrane C. Ion channels conductance regulator (CFTR) and a concomitant D. sodium hyperabsorption. 3. Which of the following maintains the difference All of the choices are mechanisms on how substances in the composition between the intracellular and pass through the phospholipid bilayer. extracellular compartments of the cell? A. Transporters D B. Gap junctions C. Ion channels D. All of the above 4. Release of neurotransmitters in the synaptic Eg. Acetylcholine enters the cell from the synaptic cleft via cleft which are contained in the vesicles is endocytosis an example of? A. Exocytosis A B. Endocytosis C. Phagocytosis D. Pinocytosis Passive transport does not require energy as 5. What is the main difference between passive and active transport? substances move along their concentration or electrical A. The need for energy in active transport because it is against concentration gradient A gradient, while active transport requires energy to move B. The need for energy in passive transport substances against their gradient. because it is against concentration gradient BIOCHEMISTRY MEMBRANE: STRUCTURE AND FUNCTION PAGE 6 of 6