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Membrane Fusion

Membrane Fusion. Membrane Fusion. Author: Judith M. White Source : Science, New Series, Vol. 258, No. 5084 (Nov. 6, 1992 ), pp. 917-924 Published by: American Association for the Advancement of Science Stable URL: http://www.jstor.org/stable/2881663 . . Introduction.

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Membrane Fusion

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  1. Membrane Fusion

  2. Membrane Fusion Author: Judith M. White Source: Science, New Series, Vol. 258, No. 5084 (Nov. 6, 1992), pp. 917-924 Published by: American Association for the Advancement of Science Stable URL: http://www.jstor.org/stable/2881663 .

  3. Introduction • Ubiquitous cell biological process • Part of many house keeping functions • Endocytosis • Constitutive secretion • Recycling • Specialization of cells • Sperm-egg fusion • Exocytosis of hormones, neurotransmitters, enzymes

  4. Introduction • Role in disease • Giant cells during inflammatory response • Viral entry into host cells • Induced cell-cell fusion by HIV • Several types of fusion events

  5. Influenza HA-Mediated Membrane Fusion • Reasons for being a model for study • Single gene product • Easily induced by pH change • Easily produced • X-ray structure known • Large database of cloned sequences • Numerous characterized mutants

  6. Influenza HA-Mediated Membrane Fusion • Hemagglutinin (HA) • Trimer of identical subunits • Conserved, hydrophobic fusion peptide in stem of each subunit • Slight mutations in structure alter or abolish fusion capabilities • Receptor binding sites lie at distal tip of protein (globular head)

  7. Influenza HA-Mediated Membrane Fusion • Fusion Steps • Fusion peptides, induced by low pH, destabilize viral and target bilayers • Conformational changes in HA trimer (rotational and lateral movements) after initial binding to receptor • Hemifusion followed by full fusion to form fusion pore

  8. Exocytosis of Mast Cell Granules • Fusion of intracellular storage vesicle with the cytoplasmic face of the plasma membrane. • The mast cell releases a mixture of compounds, including histamine, proteoglycans, serotonin, and serine proteases from its cytoplasmic granules. (inflammatory response to allergen)

  9. Exocytosis of Mast Cell Granules • Fusion Steps • Outward current transient (release of Ca2+)—discharge of vesicle membrane potential through nascent pore • Increase in cell membrane capacitance due to interaction with vesicle (directly proportional to surface area • Narrow conducting pore forms (2-2.5 nm)—width of 10 water molecules • Pore grows in concurrence with capacitance until it reaches a plateau level

  10. Intra-Golgi Transport • Membrane fusion essential for membrane trafficking of macromolecules • Studied through careful application of inhibitors

  11. Intra-Golgi Transport • Steps in Transportation Between Cisterna • Nascent coated bud forms on the donor cisterna and detaches • Targeted and attaches to acceptor cisterna • Vesicle is uncoated and matures • Fuses with acceptor cisterna • Deposits contents

  12. Intra-Golgi Transport • Requirements • ATP and GTP for vesicle budding • GTP hydrolysis for uncoating • Fatty AcylcoA for budding and maturation • Ca2+ cofactor for late transport • GTPases (monomers and trimers) and phosphoproteins for fidelity, timing, and vector

  13. Intra-Golgi Transport • Fusion Machine • 3 Proteins • Homotetramer NSF (NEM-sensitive factor) • SNAP (Soluble NSF Attachment Protein) • Integral Membrane Receptor (SNARE)

  14. Membrane Fusion • Still a lot to learn!!! • Pores developed during influenza-mediated fusion and exocytosis of mast cell granules • Complex fusion machine utilized during intra-Golgi transport (unknown if pore forms) • Why is this complexity necessary for membrane fusion events to occur?? • It is possible that the fusion pore is element that units all fusion events—viral and cell-cell fusion, regulated exocytosis, intra-Golgi transport, and other intracellular fusion events

  15. For the exam… • Identify when membrane fusion occurs in cells • Why is it necessary?

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