Molecular Transport - Transport of Macromolecules Lecture Notes PDF

Associate professor Zanda Daneberga Molecular transport - Transport of macromolecules 1 Macromolecules ◼ A large complex molecule, such as nucleic acids, proteins, carbohydrates, and lipids, with relatively large molecular weight. ◼ Transmembrane protein...

Associate professor Zanda Daneberga Molecular transport - Transport of macromolecules 1 Macromolecules ◼ A large complex molecule, such as nucleic acids, proteins, carbohydrates, and lipids, with relatively large molecular weight. ◼ Transmembrane proteins, carrier proteins and pumps are not able to ensure transport of macromolecules. ◼ Eukaryotic cells are able to take up macromolecules and particles from the surrounding medium by a distinct process – endocytosis - the uptake of extracellular material in vesicles formed from the plasma membrane. 2  Endocytosis Receptor mediated Pinocytosis endocytosis (not specific) (specific) Clathrin-mediated endocytosis Phagocytosis 3 Pinocytosis ◼ Type of endocytosis in which soluble materials are taken up from the environment and incorporated into vesicles for digestion. 4 Pinocytosis - continued 5 Receptor mediated endocytosis - Phagocytosis ◼ A special form of endocytosis in which large particles such as microorganisms and dead cells are transported into the cell via large endocytic vesicles called phagosomes. Binding of particle to receptors on the surface of cell triggers the extension of pseudopodia (actin-based movement of the cell surface). Fusion of pseudopodia forms phagosome. The phagosomes then fuse with lysosomes, producing phagolysosomes. 6  Phagocytosis - continued Acquired from: https://www.mechanobio.info/ MBInfo © 2018 National University of Singapore. 7 Phagocytosis - continued ◼ In mammals, three classes of white blood cells act as professional phagocytes — macrophages, neutrophils, and dendritic cells. 8 Receptor mediated endocytosis ◼ The selective uptake of macromolecules that bind to cell surface receptors. Receptors are concentrated in clathrin- coated pits. ◼ Specific region of plasma membrane is coated with the protein clathrin on its cytosolic face. Such regions are continually forming and budding off by endocytosis to form intracellular clathrin-coated vesicles containing extracellular fluid and the materials dissolved in it. 9 Receptor mediated endocytosis - continued 10 Receptor mediated endocytosis example - Uptake of cholesterol ◼ Cholesterol is transported through the bloodstream in the form of lipoprotein particles, the most common of which is called low-density lipoprotein (LDL). 11 LDL receptor and human pathology ◼ Familial hypercholesterolemia (MIM #143890) Patients with this disease have very high levels of serum cholesterol and suffer heart attacks early in life. Caused by allelic variant in LDLR gene (other genes may be involved). 12 The LDL receptor 13 Clathrin-coated pits 14 Clathrin-coated vesicles 15 Exocytosis ◼ Exocytosis is the process by which the cell secreted molecules are released into the extracellular fluid. 16  Exocytosis Constitutive Regulated exocytosis exocytosis 17 Constitutive exocytosis ◼ Carried out by all cells and serves to transfer molecules from the Golgi network to the outer surface of the cell. ◼ Most proteins are transported directly to the cell surface by the nonselective constitutive secretory pathway (does not require a particular signal). 18 19 Regulated exocytosis ◼ Regulated secretion occurs in response to specific conditions, signals or biochemical triggers, and is the process underlying the release of cytokines, hormones, neurotransmitters and other small signalling molecules. ◼ Secretory proteins are packed into secretory vesicles. 20 21  Example of regulatory exocytosis ◼ The release of insulin by β cells of the Langerhans pancreatic islets into the response to variations in blood glucose concentration. ◼ Insulin is retained in secretory vesicles that are triggered to fuse with the plasma membrane in response to a rise in intracellular Ca+ concentration: A rise in blood glucose causes the ATP:ADP ratio in the β cell to rise, which closes a K+ channel in the plasma membrane. The resulting change in the β cell's membrane potential opens a Ca2+ channel, causing a rise in intracellular Ca2+ concentration and the secretion of insulin. 22 23 Exocytosis - continued ◼ Secretory vesicle fuses with the plasma membrane, contents are discharged from the cell by exocytosis, and its membrane becomes part of the plasma membrane. ◼ Membrane components from secretory vesicles are removed from the surface by endocytosis almost as fast as they are added by exocytosis. ◼ The balance between the forward and retrograde flows of membrane needs to be precisely regulated. This mechanism is still not clear. 24 Diversity of vesicles ◼ Transport processes mediate a continual exchange of components between the chemically distinct, membrane- enclosed organelles. ◼ The assembly of the coat helps to collect specific membrane and soluble cargo molecules for transport and to drive the formation of the vesicle. 25  Diversity of vesicles - continued ◼ Clathrin-coated vesicles - mediate transport from the plasma membrane and the trans Golgi network. ◼ COPI- and COPII-coated vesicles - mediate transport between the ER and the Golgi apparatus and between Golgi cisternae. ◼ Before the vesicle fuses with a target membrane, the coat is discarded, to allow the two cytosolic membrane surfaces to interact directly and fuse. 26