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Principal Investigator: Jack H Freed
Organization: CORNELL UNIVERSITY
Fiscal Year: 2020
Award: $494,198
Funding agency: National Institute of General Medical Sciences
Abstract: This project is aimed at the study of properties of membrane proteins that underlie important
biomedical processes and are implicated in health disorders and how they interact with their membrane
environments. By means of the latest one and two dimensional electron-spin resonance (ESR) methodologies,
including Pulse-Dipolar ESR (PDS), multifrequency ESR, and Two-Dimensional Electron-Electron Double
Resonances (2D-ELDOR), as well as site-directed nitroxide spin-labeling methods, we will directly observe
significant protein functional changes and in parallel experiments, observe the concomitant changes occurring
in the dynamic structure of the lipid bilayers. This ability to accurately characterize both membrane and
membrane protein is an innovative approach toward understanding on the role of membrane-protein
interactions affecting the protein's function. Specific projects include the following. First, we will advance our
study of the mechanism of viral membrane fusion, based on our previous success in detecting the membrane
ordering effect of influenza and HIV glycoprotein fusion peptides (FP). We will extend this study to the structure
of their FP-transmembrane domain complex in membranes and to quantification of the induced microdomain,
plus we shall extend the study to SARS and gamete membrane fusogens. In the second project, the tau
protein, which plays an important role in neurodegeneration, will be studied. We have shown how tau interacts
with membranes and adopts different conformations in response to the curvature of liposomes, so we plan to
study the interaction between tau and microtubules, which directly addresses its functional and pathological
roles in neurodegenerative diseases. The third project will focus on the structure of asymmetric membranes,
which are crucial for cell function. We will investigate how both membrane leaflets interact with each other, and
how the changes in the composition of one leaflet affect ordering and fluidity of the other, as well as how the
model peptide gramicidin changes their structure and facilitates lipid flip-flop. In the fourth project, we will study
the influenza A M1 and M2 matrix proteins, which are related to viral infectivity and proliferation. We previously
showed the oligomerization of M2 TMD in membrane is a two-step process and the stoichiometry is affected by
ligand binding. We will focus on the effect of lipid composition on the M1 oligomerization. We will also study the
structure of the M1-M2 complex in membranes. In the fifth project, our ESR studies on the mechanism of
transmembrane signaling in bacterial chemoreceptors will be continued and extended. We will 1) characterize
the lipid dependence of the piston motion exhibited by chemoreceptors, 2) examine the effect of receptor
oligomerization state and conformation on lipid structure, and 3) probe the interactions of the chemoreceptor
sensing domain relative to the lipid bilayer. All these studies will involve extensive collaborations with leading
research groups. Possible clinical applications include detection of membrane changes during immune
response, prevention of viral entry, fertility diseases, neurological disorders, and development of antimicrobials.
Terms: <2-dimensional><AD dementia><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adopted><Affect><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease dementia><Alzheimers Dementia><Alzheimers disease><Antiviral Agents><Antiviral Drugs><Antivirals><Bacterial Infections><Bilayer Fluidity><Binding><Blood Plasma Cell><C-terminal><Cannot achieve a pregnancy><Cell Body><Cell Communication and Signaling><Cell Function><Cell Membrane Lipids><Cell Process><Cell Signaling><Cell membrane><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemoreceptors><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><Collaborations><Complex><Coronavirus glycoprotein S><Coronavirus spike protein><Cytoplasmic Membrane><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Dependence><Detection><Development><Difficulty conceiving><Disease><Disorder><Drug Targeting><EPR spectroscopy><ESR Spectroscopy><Electron Paramagnetic Resonance><Electron Spin Resonance><Electron Spin Resonance Spectroscopy><Electrons><Environment><Environmental Factor><Environmental Risk Factor><Exhibits><Fecundability><Fecundity><Fertility><Fertility Agents><Fertility Drugs><Filament><Gametes><Germ Cells><Germ-Line Cells><Glycoproteins><Gramicidin><Grippe><HAP2><HIV><Health><Human Immunodeficiency Viruses><Huntingtin-Associated protein 1><Immune response><Immunological response><Infertility><Infertility Agents><Infertility Drugs><Influenza><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Integral Membrane Protein><Intracellular Communication and Signaling><Intrinsic Membrane Protein><Isoforms><LAV-HTLV-III><Lead><Length><Ligand Binding><Lipid Bilayers><Lipids><Liposomal><Liposomes><Lymphadenopathy-Associated Virus><MT-bound tau><Membrane><Membrane Fluidity><Membrane Fusion><Membrane Lipids><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Methodology><Methods><Micro-tubule><Microtubules><Modeling><Modernization><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Motion><N-terminal><NH2-terminal><Negative Beta Particle><Negatrons><Nerve Degeneration><Nervous System Degenerative Diseases><Nervous System Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Organization Charts><Orthomyxovirus Type A><Paramagnetic Resonance><Pathologic><Pb element><Peptides><Physiologic pulse><Plasma Cells><Plasma Membrane><Plasmacytes><Play><Prevention><Primary Senile Degenerative Dementia><Process><Proline-Rich Domain><Proline-Rich Region><Property><Protein Isoforms><Proteins><Pulse><Receptor Protein><Relaxation><Reproductive Cells><Research><Role><SARS><SARS Virus><SARS corona virus><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-Related Coronavirus><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Sex Cell><Signal Transduction><Signal Transduction Systems><Signaling><Site><Specificity><Spin Labels><Structural Models><Structural Protein><Structure><Study models><Subcellular Process><Surface Proteins><TM Domain><Tars><Techniques><Testing><Transmembrane Domain><Transmembrane Protein><Transmembrane Protein Gene><Transmembrane Region><Tubulin><Type A Influenza><Viral><Viral Diseases><Virion><Virus><Virus Diseases><Virus Particle><Virus-HIV><abnormally aggregated tau protein><anti-microbial><anti-viral agents><anti-viral drugs><anti-virals><antimicrobial><bacteria infection><bacterial disease><base><biological signal transduction><clinical applicability><clinical application><conformation><conformational state><coronavirus S protein><coronavirus spike glycoprotein><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><dementia of the Alzheimer type><developmental><drug development><electron paramagnetic resonance spectroscopy><environmental risk><experiment><experimental research><experimental study><fertility cessation><fertility loss><fertility medicine><fertility promoting drug><filamentous tau inclusion><flu infection><fluidity><heavy metal Pb><heavy metal lead><host response><immunoresponse><infertile><influenza infection><initial cell><innovate><innovation><innovative><lipid bilayer membrane><lipid structure><membrane model><membrane structure><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><nano disk><nanodisk><nervous system disorder><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neurological disease><neuronal degeneration><organizational structure><paired helical filament of tau><physical property><plasmalemma><plasmocyte><primary degenerative dementia><protein function><protein protein interaction><protein structure><protein structures><proteins structure><receptor><response><self-aggregate tau><senile dementia of the Alzheimer type><severe acute respiratory syndrome-CoV><sexual cell><social role><stoichiometry><success><tau><tau MT binding domain><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau conformation><tau factor><tau fibrillization><tau filament><tau function><tau interaction><tau microtubule binding domain><tau microtubule interaction><tau neurofibrillary tangle><tau oligomer><tau paired helical filament><tau polymerization><tau-MT interaction><tau-microtubule interaction><tau-tau interaction><two-dimensional><viral infection><virus infection><virus-induced disease><τ Proteins><τ aggregation><τ conformation><τ function><τ interaction><τ microtubule binding domain>