CR

Chapter 1-5: Introduction to Biological Membranes

Review of Previous Week

  • Proteins:

    • Discussed protein structure at primary, secondary, tertiary, and quaternary levels. The primary structure is the linear sequence of amino acids, dictated by genetic code. The secondary structure involves local folding patterns like alpha-helices or beta-pleated sheets, stabilized by hydrogen bonds between backbone atoms. The tertiary structure is the overall three-dimensional shape of a single polypeptide chain, resulting from interactions between R-groups (side chains), including hydrophobic interactions, ionic bonds, hydrogen bonds, and disulfide bridges. The quaternary structure applies to proteins composed of multiple polypeptide chains (subunits).

    • Dedicated a lecture to enzymes, which are biological catalysts, almost all of which are proteins. Enzymes accelerate biochemical reactions by lowering the activation energy without being consumed in the process. Their specificity for substrates arises from their unique active site structures.

  • Nucleotides:

    • Covered polynucleotides, specifically DNA (Deoxyribonucleic Acid) and RNA (Ribonucleic Acid), which store and transmit genetic information. DNA forms a double helix, and RNA typically exists as a single strand with diverse functions.

    • Explored biological functions of small nucleotides:

      • ATP (Adenosine Triphosphate): The primary energy currency of cells. Hydrolysis of the terminal phosphate bond to form ADP (ATP \to ADP + P_i) releases a substantial amount of free energy (\approx -7.3 \text{ kcal/mol}), which is used to power various cellular activities, including muscle contraction, active transport, and biosynthesis.

      • Cyclic AMP (cAMP): A crucial second messenger molecule involved in intracellular signal transduction. Typically present at low concentrations, its levels rapidly increase in response to diverse external stimuli (e.g., hormones and neurotransmitters binding to G-protein coupled receptors) by the enzyme adenylyl cyclase. cAMP then activates protein kinase A (PKA), leading to phosphorylation of target proteins and a cascade of cellular responses, playing roles in cellular communication, metabolism, and gene expression.

Introduction to Biological Membranes

  • This week's focus is entirely on biological membranes, which define cells and compartmentalize eukaryotic cell functions.

  • Today and tomorrow will cover membrane structure: what membranes look like, what they're made from, and their fundamental physical and chemical behavior, emphasizing the lipid bilayer and associated proteins.

  • The subsequent lecture will detail functions of biological membranes, including transport, signaling, and cell-cell recognition.

  • The final lecture will revisit Cystic Fibrosis as a review, connecting it to concepts covered over the three weeks, particularly membrane protein function and genetic disorders.

Cystic Fibrosis: A Membrane-Related Disorder

  • Cystic Fibrosis (CF): An inherited genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein.

  • Location: This essential protein resides in the surface membrane of epithelial cells, which line various body cavities, ducts, and surfaces (e.g., lungs, pancreas, sweat glands, intestines).

  • Protein Function: The defective CFTR protein, a type of ABC (ATP-binding cassette) transporter, normally functions as a chloride ion (Cl^-) channel, regulating the flow of chloride ions across the cell membrane. In healthy individuals, CFTR also facilitates bicarbonate (HCO_3^-) transport. When CFTR is defective or absent, chloride and bicarbonate transport is impaired.

  • Consequences of Defective CFTR: Reduced chloride and bicarbonate secretion leads to a buildup of thick, sticky mucus on epithelial surfaces, particularly in the respiratory and digestive tracts. This abnormal mucus traps bacteria, leading to chronic lung infections, inflammation, and progressive lung damage. It also blocks pancreatic ducts, preventing digestive enzymes from reaching the intestine, causing malabsorption of nutrients.

  • Representation: Textbooks often show a simplified diagram of the membrane, the protein, and chloride flowing through to illustrate the basic concept.

  • Actual Protein Structure: Proteins are not simple spheres; they possess highly intricate three-dimensional structures critical for their function. The alpha fold prediction of the CFTR protein structure, an advanced computational method, reveals its typical secondary structures:

    • Alpha helices: Coils visible in the structure, often forming transmembrane domains that span the lipid bilayer.

    • Beta pleated sheets: Flat, extended structures, commonly found in soluble domains or lining aqueous pores.
      These secondary structures are common features of many proteins, providing stability and functional motifs, including in the CFTR protein.

  • The detailed structure, gating mechanism, and pharmacology of the CFTR protein, including current therapeutic strategies, will be discussed in detail in the last lecture.

General Membrane Concepts

  • Plasma Membrane:

    • The outer boundary of every cell, enclosing the cytoplasm and separating the cell's interior from its non-living external environment.

    • Exhibits selective permeability, meaning it precisely controls which substances can enter or exit the cell. Small, nonpolar molecules (e.g., O2, CO2) can diffuse freely, while large polar molecules (e.g., glucose) and ions (Na^+, K^+, Cl^-) require specific transport proteins to cross. This property is crucial for maintaining cellular homeostasis.

    • Primary Function: To establish and maintain a distinct internal environment (cytosol) that differs significantly in its biochemical and ionic composition from the outside world (e.g., interstitial fluid, blood plasma). This difference is vital for metabolic processes and cellular signaling.

    • Serves as a permeability barrier, tightly controlling the traffic (movement of substances) across it through various transport mechanisms, including passive diffusion, facilitated diffusion, and active transport.

  • Internal Membranes (Organelles):

    • Eukaryotic cells are characterized by the presence of internal membrane-bound compartments called organelles (e.g., nucleus, endoplasmic reticulum, Golgi apparatus, lysosomes, mitochondria, peroxisomes).

    • Organelle membranes allow their interior environment to differ significantly from the surrounding cytoplasm. This compartmentalization is critical for:

      • Specialized environments: Creating unique biochemical conditions necessary for specific reactions. For example, some biochemical reactions require a highly acidic environment (pH \approx 4.5-5.0), such as those catalyzed by hydrolytic enzymes in lysosomes. Partitioning these reactions into acidic organelles prevents the entire cell's cytosol (pH \approx 7.2) from becoming acidic, which would damage other cellular components.

      • Increased efficiency: Concentrating reactants and enzymes, and segregating incompatible reactions.

    • Each organelle membrane also exhibits selective permeability, regulated by specific transporters and channels.

  • Fluid Mosaic Model:

    • The widely accepted theoretical framework describing the fundamental, similar structure of both cell surface and organelle membranes, first proposed by Singer and Nicolson in 1972.

    • Schematic Representation: Depicts the membrane as a dynamic, fluid structure, primarily composed of a phospholipid bilayer with various proteins embedded in or associated with it.

      • Lipids: Represented by red heads (hydrophilic phosphate head groups) with yellow tails (hydrophobic fatty acid chains), forming the basic bilayer. These include phospholipids, cholesterol (which modulates membrane fluidity), and glycolipids.

      • Proteins: Represented by blue elements, they are diverse in type and function. Integral (transmembrane) proteins span the entire lipid bilayer, often forming channels or receptors. Peripheral proteins are loosely associated with the membrane surface, often involved in signaling or anchoring. Lipid-anchored proteins are covalently attached to lipids embedded in the bilayer.

      • Sugar chains (carbohydrates): Typically found on the outer surface of the plasma membrane, covalently linked to either lipids (forming glycolipids) or proteins (forming glycoproteins). These form the glycocalyx and play crucial roles in cell-cell recognition, adhesion, and as receptors.

    • "Fluid" Aspect: Refers to the lateral mobility of both lipids and proteins within the plane of the membrane. Phospholipids can move rapidly laterally, rotate, and flex their fatty acid chains. Proteins can also move laterally, though often more slowly and sometimes restricted by anchoring to the cytoskeleton. This fluidity is essential for membrane function (e.g., cell division, cell signaling, membrane fusion).

    • "Mosaic" Aspect: Refers to the diverse assortment of proteins embedded in or associated with the lipid bilayer, resembling a mosaic pattern. The specific arrangement and types of proteins vary depending on the membrane's specific function and location.

Membrane Lipids

  • Basic Lipid Construction:

    • Starts with glycerol: A small three-carbon molecule (C3H8O_3) with three hydroxyl (-OH) groups, one on each carbon. Glycerol serves as the backbone for many lipids.

    • Fatty acid: A long hydrocarbon chain (typically 12-24 carbons) with hydrogens, ending with a carboxylic acid group (-COOH).

      • Example: Palmitic acid has 16 carbons and is a saturated fatty acid (no double bonds).

    • Bond Formation: A fatty acid forms a covalent ester bond with a hydroxyl group on glycerol. This reaction is a dehydration reaction (or condensation reaction), where a molecule of water is released for each ester bond formed. One, two, or three fatty acids can attach to glycerol, forming mono-, di-, or triglycerides.

  • Polarity of Fatty Acids:

    • Hydrocarbon tail: The long chain of carbons and hydrogens is non-polar (hydrophobic).

      • Reason: Carbon-carbon bonds are non-polar because electrons are shared equally. Carbon and hydrogen have very similar electronegativity (about 2.5 and 2.1, respectively), resulting in approximately equal electron sharing in C-H bonds. The symmetrical distribution of these numerous non-polar bonds makes the overall hydrocarbon tail non-polar and insoluble in water.

    • Carboxylic acid group (at the end of a free fatty acid): Contains highly electronegative oxygen atoms (C=O and O-H bonds), making this part polar and weakly acidic. In aqueous solution, the carboxyl group can ionize (-COO^-), becoming even more hydrophilic.

  • Phospholipids: The Building Blocks of Membranes:

    • The most abundant class of lipids in biological membranes, forming the fundamental bilayer structure.

    • Structure: Glycerol backbone linked to two fatty acid tails via ester bonds and a phosphate group (often with an additional small polar molecule like choline, ethanolamine, or serine) via a phosphodiester bond. This creates a distinctive amphipathic structure.

    • Amphipathic molecules: Possess both a non-polar (hydrophobic) end and a polar (hydrophilic) end. Specifically:

      • Hydrophilic Head: Consists of the phosphate group and any attached polar molecule. This region is charged and readily interacts with water.

      • Hydrophobic Tails: Composed of the two long hydrocarbon fatty acid chains. These tails repel water and readily interact with other hydrophobic molecules.

    • In aqueous environments, the amphipathic nature of phospholipids drives their spontaneous self-assembly into a lipid bilayer, where the hydrophilic heads face the aqueous surroundings, and the hydrophobic tails are sequestered in the interior of the membrane, away from water. This bilayer forms an effective barrier to water-soluble molecules and ions, establishing the basic structural framework of all biological membranes.