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Biol 205 Spring 2008 Week 3 Lecture 2 REading Assignment: Chapter 12 Membrane Transport pgs. 389-393 & Figure 12-7 on pg 394 The Lives of the Cell by Lewis Thomas “ … It takes a membrane to make sense out of disorder in biology. You have to be able to catch energy and hold it, … releasing it in small shares……. To stay alive, you have to be able to hold out against equilibrium, maintain imbalance, bank against entropy and you can only transact this business with membranes in our kind of world…..” 1 Maintaining an orderd structure: membranes, of course, define the cell itself and the subcellular compartments found in a eukaryotic cell Identify each of these subcellular structures Answers on last page of lecture notes 10 = garbage disposal/recycler 7 = network of protein filaments (Ignore 4 & 12) 2 Many activities of living cells take place on or across membranes: • Defining and maintaining an ordered compartment • Receiving and transducing environmental signals: known as Signal transduction • Mediating Cell-cell interactions • Capturing & transforming energy • Storing potential energy in the form of ion or solute asymmetries established and maintained by membrane associated proteins 3 A preview of the plasma membrane All biological membranes have a common general structure: a thin film of lipid and protein molecules held together by noncovalent interactions cell membranes are dynamic and fluid and most molecules can move about in the plane of the membrane 4 LIPIDS: • large biological molecues that have little affinity for water • are NOT polymers • consist mostly of hydrocarbons • include fats, steroids and phospholipids 5 Phospholipids are the most abundant lipid in the membrane Phospholipids are amphipathic: • hydrophilic region and a hydrophobic region: Figure 4.4a Phospholipid Formula Schematic Space-filling Icon NH3+ HC COOH Polar head (hydrophilic) CH2 O– O P O– H O C CH2 O O Nonpolar tail (hydrophobic) CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH3 Glycerol OC O CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH3 Fatty acid C CH2 CH2 CH2 Phosphate Fatty acid H2C Serine What happens when phospholipids are mixed with water? 6 Would a bilayer form is there was no hydrophilic head on the molecule? 7 Proteins are imbedded in membranes Nature 438: 578 2005 Membranes are more mosaic than fluid 8 Proteins are imbedded in membranes 9 THE TRANSACTIONS OF THE CELL MEMBRANE Controls molecular traffic into and out of cell: which molecules and particles enter and exit the cell Transduces signals from outside to inside of the cell Mediates the physical interactions between animal cells Mediates many enzymatic reactions including those involving energy transformation in the chloroplast and mitochondria 10 Features of the plasma membrane the thin film of lipid and protein molecules held together by noncovalent interactions membranes are dynamic and fluid and most molecules can move about in the plane of the membrane Membrane fluidity is important for many reasons: • enables membrane proteins to diffuse rapidly in the plane of the bilayer and to interact with one another • provides a simple means of distributing lipids and proteins by diffusion from sites where they are added to the bilayer • allows membranes to fuse with one another and mix their molecules -- important for many cellular events 11 What factors might affect membrane fluidity? 12 Membrane fluidity is determined by: • temperature • the nature of the hydrocarbon tails on phospholipids • presence of steroid molecules such as cholesterol (present in animals and absent in plants, yeast and bacteria) 13 Vegetable Oil versus Butter ? What’s the difference? 14 15 The kink resulting from the double bond is exaggerated for emphasis 16 The fluidity of a membrane • __________ with increasing amounts of saturated hydrocarbon tails: these can pack tightly together and are ____ fluid as a result • _________with increasing amount of unsaturated hydrocarbons: kinks in the tail introduced by C=C _______ close packing of the hydrocarbon tails The fluidity of a membrane • varies ____________ with the length of the hydrocarbon tail • decreases with increasing amounts of cholesterol: short, rigid molecule which modulates the fluidity of the bilayer 17 Cholesterol • common component of animal cell membranes • cholesterol is a type of steroid • steroids are lipids consisting of four fused rings 18 19 • cholesterol decreases membrane fluidity because its rigid steroid ring system interferes with the motions of the hydrocarbon chains in the phospholipids • but it also inhibits the close packing of the hydrocarbon chains animations showing effect of cholesterol http://telstar.ote.cmu.edu/biology/MembranePage/index2.html 20 Proteins can associate with the plasma membrane Various ways in which membrane proteins can associate with the lipid bilayer. Most transmembrane proteins are thought to extend aacross the bilyaer as a (1) single alpha helix, (2) as multiples alphas helices, or (3) as a rolled-up beta sheet. 21 22 How can a protein be imbedded in the hydrophobic interior of a membrane? 23 24 Functions of integral membrane proteins: • Transport proteins: control molecular traffic into and out of cell • Enzymes: photosynthesis and respiration • Transduce signals from outside to inside of the cell: • transduction of polypeptide hormone signals • transduction of nerve impulses between cells • many other processes • Mediate the physical interactions between animal cells (cell adhesion): form intercellular junctions • Attach to the cytoskeleton 25 MEMBRANES: So WHAT? Woe to that child which when kissed on the forehead tastes salty. He is bewitched and soon must die. This adage, from northern European folklore, is an early reference to the common genetic disease recognized today as cystic fibrosis. As the saying implies, the disorder once routinely killed children in infancy and is often identifiable by excessive salt in sweat.. (Scientific American Dec. 1995) cystic fibrosis: most common severe recessive monogenic disorder affecting people of European descent Info about cystic fibrosis http://www.nlm.nih.gov/medlineplus/cysticfibrosis.html http://ghr.nlm.nih.gov/condition=cysticfibrosis 26 The “cystic fibrosis” gene codes for a transmembrane protein involved in chloride transport (note gene is named for its mutant phenotype and not for the protein that it specifies) These figures illustrate the domain structure of the protein CFTR= cystic fibrosis transmembrane conductance regulator CFTR= a chloride channel PREVIEW: This gene is 270 kb long but the mRNA is only 6129 bp long 27 To understand the significance of this defect we need to first consider membrane permeability 28 The plasma membrane lies at the interface of the controlled interior and fluctuating exterior of a cell Membrane controls two distinct and crucial activities: • Selective Permeability: select among different molecular species, slowing down the permeation of some while allowing others to pass unimpeded • Active Transport: brings about the transport of material, either inward (accumulation) or outward (excretion, secretion) against a concentration gradient Permeate: to diffuse through or penetrate something 29 What factors control whether an atom or molecule can cross the plasma membrane? Lipid composition of the membrane: a high % of cholesterol makes a membrane less permeable to small molecules a high % of unsaturated hydrocarbon chains increases permeability Characteristics of the molecule itself SUCH AS? Presence of transporter proteins 30 The relative permeability of a synthetic lipid bilayer to different classes of molecules. The smaller the molecule and, more importantly, the less strongly it associates with water, the more rapidly the molecule diffuses across the bilayer 31 Permeability coefficients for the passage of various molecules through synthetic lipid bilayers What is the rate at which a given molecule will cross a protein-less lipid bilayer? • the smaller the molecule the more readily it will cross the membrane • more hydrophobic, the more readily it will cross the membrane 32 Nice animations on diffusion and transport http://www.wiley.com/legacy/college/boyer/0470003790/animations/membrane_transport/membrane_transport.swf Small nonpolar molecules O2: the covalent bond between the two atoms is nonpolar because the electrons are shared equally It is a small molecule and therefore it will readily dissolve in a lipid bilayer and diffuse across it CO2 also readily diffuses Small uncharged polar molecules if small enough, uncharged polar molecules such as water and ethanol will diffuse rapidly across a bilayer glycerol diffuses less rapidly Large uncharged polar molecules glucose: hardly at all Charged molecules - large or small lipid bilayers are highly impermeable to any charged molecule, no matter how small Charge and degree of hydration of such molecules prevents them from entering the hydrocarbon phase of the bilayer 33 MEMBRANE TRANSPORT PROTEINS The passage of large, polar or charged molecules requires special membrane proteins Two major classes of membrane transport proteins: Carrier proteins and channel proteins • Both form continuous protein pathways across the lipid bilayer • All membrane transport proteins are relatively specific with respect to what molecules they transport 34 Channel Proteins Forms a hydrophilic water-filled pores that extends across the lipid bilayer Specific for inorganic ions of the appropriate size and charge allowing them to cross the membrane Transport through channel proteins occurs at a much faster rate than transport through carrier proteins (discussed below) 35 Channel Proteins Pores can be open or closed Allosteric Regulation of a cation channel: Top and lateral representations of a cation channel • The channel is made of four identical blue subunits. • The orange triangles are small molecules (called cyclic nucleotides) that can bind to the subunits of the channel. 36 CFTR= cystic fibrosis transmembrane conductance regulator CFTR= a chloride channel http://www.genet.sickkids.on.ca/cftr/CftrDomainPage.html?domainName=MSD9 37 NOTE: the elegant secondary and tertiary structure All channel proteins allow the solute to cross the membane passively: down the concentration gradient This is known as passive transport or facilitated diffusion 38 Diffusion: • net drift of molecules down a concentration gradient due to random thermal movement • net random drift of molecules in the direction of lower concentration Fun web site on diffusion and osmosis: http://physioweb.med.uvm.edu/diffusion/tocpage.htm 39 A conformational change in the transporter mediates the passive movement of a solute. Carrier Proteins (aka Transporters): have a specific binding pocket for the solute to be transported; only solute molecules that fit into the binding pocket can be transported – conferring a level of specificity similar to that of the substrate-active site interaction seen with enzymes The transporter shown can exist in two conformational states: in state A, the binding sites for solute are exposed on the outside of the lipid bilayer; in state B, the same sites are exposed on the other side of the bilayer. The transition between the two states can occur randomly. It is completely reversible and does not depend on whether the solute binding site is occupied. Therefore, if the solute concentration is higher on the outside of the bilayer, more solute binds to the transporter in the A conformation than in the B conformation, and there is a net transport of solute down its concentration gradient (or, if the solute is an ion, down its electrochemical gradient). 40 Transport animations http://www.wiley.com/legacy/college/boyer/0470003790/animations/membrane_transport/membrane_transport.swf passive transport or facilitated diffusion: channel or carrier-mediated diffusion down the a concentration gradient active transport: carrier mediated active pumping of certain solutes across membrane against their concentration gradient active transport is tightly coupled to a source of metabolic energy 41 Three ways of driving active transport. The actively transported molecule is shown in yellow, and the energy source is shown in red. Coupled transport uses potential energy in the form of one solute gradient (see next page) to drive the movement of another solute against its concentration gradient 42 Ion Transport across cell membranes is of central importance in biology: • Cells maintain an internal ion concentration that is different from that of the fluid around them • These ion gradients are critical to a number of cellular processes Comparison of Ion Concentrations Inside and Outside of a Typical Mammalian Cell Component Cations: Na+ K+ Mg++ Ca++ H+ Intracellular Concentration (mM) Extracellular Concentration (mM) 5-15 140 0.5* 10-7* 7 X10-5 [10-7.2M = pH 7.2] 145 5 1-2 1-2 4 X 10-5 [10-7.4 or pH 7.4] Anions Cl5-15 110 Fixed Anions** high 0 * concentrations of free ions in the cell; the total cellular concentration is much higher ** negatively charged small and large organic molecules that are trapped inside the cell unable to cross the plasma membrane 43 OPTIONAL STUFF HOW TO LET A BIG ION THROUGH WITHOUT LETTING A SMALLER ION OF THE SAME CHARGE THROUGH K+ ions are attracted to the selectivity filter of the Potassium Channel by the electrostatic potential set up by amino acids with a negative charge. Focused around the Channel's entrance, the negatively charged amino acids also repels anions, therefore increasing the concentration of cations (K+) at the pore's entrance. Around the channel water molecules surround the cations, keeping them stable. The selectivity filter is not big enough to accommodate an ion and its water molecules. Therefore, before any ion can enter the selectivity filter it must lose all of its water molecules. However, to enter the selectivity filter the ion must remain stable. Oxygen atoms in the backbone act as surrogate water for K+ ions, keeping them stable. The smaller Na+ ion is not big enough for the oxygen atoms to act as surrogate water and stabilize it. Therefore, only K+ ions can enter the selectivity filter and remain stable. 44 45 46