Membranes and Membrane Transport PDF

Membranes and Membrane Transport  Basic Structure Phospholipid (PL) bilayer 2 antiparallel sheets of phospholipids Layer closest to the cytosol = inner leaflet Layer closest to the exterior = outer leaflet Cholesterol fits between PL layers Prote...

Membranes and Membrane Transport  Basic Structure Phospholipid (PL) bilayer 2 antiparallel sheets of phospholipids Layer closest to the cytosol = inner leaflet Layer closest to the exterior = outer leaflet Cholesterol fits between PL layers Proteins associate with the membrane  Function Establish a stable yet dynamic barrier to maintain internal environment of the cell Facilitating the biological functions of the cells Serve as attachment points for intracellular cytoskeletal Serve as attachment points for extracellular matrix Maintains a selectively permeable environment  Membrane Lipids 1. Phospholipids – The most abundant membrane lipids – Amphipathic – Polar heads point out , hydrophobic tails inwards – Length of the chain and degree of saturation impact the membrane structure – FA chains undergo motions such as flexion (bending or flexing), rotation and lateral movement – FA double bonds induce a kink reducing some types of motion and prevent FAs from packing tightly – PLs of healthy cells rarely flip-flop from one leaflet to the other 2. Cholesterol Amphipathic molecule Fits in the spaces created by the kinks in the unsaturated FA tails –decrease the ability of the FAs to move – cause stiffening/ strengthening of membrane 3. Glycolipids Lipids with attached carbohydrate CHO portion points out Function: help form the CHO coat observed on cells Involved in cell-to-cell interactions Source of blood group antigen Can act as receptors for toxins including those from cholera and tetanus  Membrane Proteins Membrane proteins Transmembrane proteins Lipid-anchored proteins Peripheral membrane proteins  Functions of Membrane proteins Cell adhesion molecules are proteins enabling cell-cell contact Ion channels Transport proteins Ligand receptors G proteins Peripheral proteins as cytoskeletal proteins Cell signalling proteins  Characteristics of membrane 1. Bilayer arrangement 2. Asymmetric a) Some PLs are found on the outer leaflet while others are more commonly seen on the inner leaflet Common distribution in most human cells –diagram b) glycolipids are differentially arranged also - Always on the outer leaflet with their attached CHO projecting away from the cell c) Glycoproteins – arranged as glycolipids d) Peripheral proteins – only inner leaflet Note: Cholesterol can flip-flop – so found on both leaflets 3. Fluid mosaic Proposed by Singer and Nicholson in 1972 to describe PMs 4. Contain lipid rafts - Specialized cholesterol-enriched microdomains within membranes Functions include cholesterol transport, endocytosis and signal transduction 3 types a) Glycosphingolipid enriched membranes (GEMs) b) Polyphosphoinositol-rich rafts c) Caveolae – flask-shaped invaginations of cell membranes containing the protein caveolin – causes a local change in morphology of the membrane  2. Transport across membranes Transport across membranes Why? to import raw materials for biosynthesis and to export waste Extracellular to translocate ions across membranes to secrete extracellular proteins Problem: lipid bilayer’s hydrophobic core prevents transport of ions, polar molecules and large proteins Intracellular  Different kinds of transport Passive: thermodynamically favorable Active: Diffusion: though the membrane not thermodynamically (small non polar molecule) favorable Facilitated diffusion: facilitated by Requires ATP directly or transporter proteins indirectly  Some transport proteins can bind more than one type of ligand. Uniport: moves one substance at a time Symport: transports two different substances Antiport: moves two different substances in different directions across the membrane © 2014 John Wiley & Sons, Inc. All rights reserved.  Type of transporters Channels (passive): – Pores: always open – Gated channel: open or close in response to a signal Transporters (passive or Active) – Conformational changes – Enzymatic activity Glucose transporter changes conformation  2. Transport across membranes Disease related to membrane transport defect Cystic fibrosis Also called mucoviscidosis Thick mucus in lungs, and other tissues Lung infections, malnutrition Excessive salt in sweat Autosomal recessive disease Ireland's most common life-threatening inherited disease (about 1 in 19 are carriers of CF mutated gene) Approx 1 in 29 of white Caucasian-Americans are carriers The most common lethal genetic disease in Caucasians 1:2,500  2. Transport across membranes Cystic Fibrosis Transmembrane conductance Regulator protein CFTR is a chloride channel It opens in response to phosphorylation Located in sweat and pancreatic ducts, gut, seminiferous tubules, conducting airways and many other tissues  2. Transport across membranes CFTR Channel  2. Transport across membranes CFTR mutations CFTR does not reaching the apical membrane or has reduced function  ΔF508 mutation Most common mutation Deletion of three nucleotides that results in a loss of the amino acid phenylalanine (F) at the 508th position on the protein two-thirds (66-70%) of CF cases worldwide and 90 percent of cases in the United States ΔF508 protein does not fold normally and is degraded by the cell. over 1,400 other mutations that can produce CF  2. Transport across membranes New drugs – treat underlying cause of CF Personalized –tailored for specific mutations 2012 – new drug approved by FDA that works on one particular mutant increasing its ability to open (Kalydeco) – R117H gene alteration (6% of CF population in Ireland) - G551D (15% of pop in Ireland) 2017- Orkambi – to Ireland 2017 Symkevi – approved in Jan 2019 Kaftrio – Oct 2020 Combination treatments  Clinical Correlation: Asymmetric membranes Phospholipids of the PM (including RBCs) are distributed asymmetrically Macrophages contain PS (phosphatidlyserine) receptors that bind, internalize and degrade PS- displaying cells Normal aging of RBCs is associated with exposure of PS on the surface of the PM – signals the macrophage system to destroy them There is evidence that the anemia and shortened life span of RBCs in certain pathological conditions such as lead intoxication and uremia in patients with renal failure could be due to increased red cell PS exposure  Clinical Correlation: Phospholipids Respiratory Distress Syndrome (RDS) RDS – major cause of neonatal morbidity and mortality in many countries Cause – prem babies develop RDS because of immaturity of lungs from deficiency of pulmonary surfactant The maturity of the fetal lung can be assessed from lecithin/sphingomyelin (L/S) ratio in amniotic fluid The ratio of 2.0 is characteristic of term birth Ratio 1.5-1.9 – 40% risk of developing RDS