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Principal Investigator: LUKAS K TAMM
Organization: UNIVERSITY OF VIRGINIA
Fiscal Year: 2022
Award: $562,219
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Membrane fusion, mediated by viral spike glycoproteins, is a key process in the infection cycle of all
enveloped human and animal viruses. The overall goal of this project is to understand the molecular
mechanisms of Ebola and human immunodeficiency virus entry by membrane fusion, by taking
combined state-of-the-art structural and cell biophysical imaging approaches. Although the crystal
structures of the ectodomains of several enveloped virus spike glycoproteins have been determined to
high resolution and although we and others have contributed NMR structures of the membrane-
interactive parts of some of these proteins over the years, we are only beginning to understand the
structural transformations that take place when these protein domains interact with membranes and
each other, and how these structures drive membrane fusion. In the previous grant period we have
made substantial progress towards elucidating the structures of the fusion loop, membrane proximal,
and transmembrane domains of the Ebola virus envelope glycoprotein and their pH-dependencies in
membrane environments. We have also discovered that HIV particles bind and fuse preferentially at
lipid discontinuities in plasma membranes of infected cells and that this process depends critically on
the level of membrane cholesterol. Building on these achievements, we now propose to (1) solve the
structure of the Ebola virus fusion loop in interaction with its membrane-proximal and transmembrane
domain, (2) determine the intracellular factors that trigger Ebola virus fusion in the late endosome, and
(3) determine the role of membrane heterogeneity in forming the fusion pore for HIV entry.
Terms: <AIDS Virus><Achievement><Achievement Attainment><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Affect><Animals><Antiviral Agents><Antiviral Drugs><Antiviral Therapy><Antivirals><Attention><Aves><Avian><Avian Influenza><Award><Binding><Biochemical><Biophysics><Bird Flu><Birds><Calcium><Cell Body><Cell Function><Cell Process><Cell membrane><Cell physiology><Cell surface><Cells><Cellular Function><Cellular Membrane><Cellular Physiology><Cellular Process><Cholesterol><Comment><Commentary><Cryo-electron tomography><Crystallization><Cytoplasmic Membrane><Dependence><Disease><Disorder><EBOV><EBOV GP><Ebola><Ebola virus><Ebola virus GP gene product><Ebola virus envelope glycoprotein><Ebola-like Viruses><Editorial Comment><Endosomes><Environment><Equine Morbillivirus><Flu virus><Fowl Pest><Fowl Plague><Funding><GP Ebola virus><GP2><GP2 gene><Genetic Alteration><Genetic Change><Genetic defect><Glycoprotein 2, Zymogen Granule Membrane><Glycoproteins><Goals><Grant><Grippe><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HTLV-III gp120><Hendra><Hendra Virus><Hereditary><Heterogeneity><Human><Human Immunodeficiency Viruses><Infection><Influenza><Influenza Virus><Inherited><Intestinal><Intestines><Knowledge><LAV-HTLV-III><Lead><Lipids><Lymphadenopathy-Associated Virus><Measles virus><Mediating><Membrane><Membrane Fusion><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mutation><Nucleic Acids><Organelles><Pathway interactions><Pb element><Peer Review><Peptide Domain><Plasma Membrane><Play><Preparation><Process><Protein Domains><Proteins><Proteolytic Clipping><Proteolytic Processing><Publications><Published Comment><Publishing Peer Reviews><Receptor Activation><Receptor Protein><Receptosomes><Research><Resolution><Role><Scientific Publication><Site><Structure><Structure-Activity Relationship><Subcellular Process><TM Domain><Tertiary Protein Structure><Testing><Transmembrane Domain><Transmembrane Region><Transmission><Viewpoint><Viral><Viral Diseases><Viral Envelope Proteins><Viral Fusion Proteins><Virus><Virus Diseases><Virus-HIV><Work><ZIKV><Zika Virus><Zymogen Granule Membrane Glycoprotein 2><airway aerosol><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-viral therapy><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><avian flu><biophysical foundation><biophysical principles><biophysical sciences><block viral entry><bowel><chemical structure function><conformation><conformational state><cryo-EM tomography><cryoEM tomography><cryoelectron tomography><ebolavirus><electron cryo-tomography><genome mutation><gp120><gp120 ENV Glycoprotein><gp120(HIV)><heavy metal Pb><heavy metal lead><high resolution imaging><imaging approach><imaging based approach><influenza in birds><influenzavirus><inhibit viral entry><late endosome><light microscopy><live cell microscopy><membrane structure><particle><pathway><plasmalemma><programs><receptor><receptor binding><receptor bound><respiratory aerosol><rougeole virus><rubeola virus><social role><structure function relationship><transmission process><viral entry blocker><viral entry inhibitor><viral infection><viral infectious disease treatment><virus envelope><virus infection><virus-induced disease><zikav>