This work is aimed at developing greater understanding of the dynamic molecular properties, as well as the structure, function, and association, of model and biological membranes, bioactive peptides, and membrane proteins that underlie important biological processes or are implicated in health disorders, and the latest one and two-dimensional electron-spin resonance (ESR) technologies will be employed to better address these issues. Specific projects include the following: The study of the dynamic domain structure of the plasma membrane in live RBL-2H3 (and other related cells) and plasma membrane vesicles (PMV) will be employed to correlate the change in domain structure with signaling by the IgE receptor after activation by antigen to test the hypothesis that receptor activation is modulated by the domain structure of the surrounding lipids. This study will be based on recent results, which showed the existence of Liquid-ordered and Liquid-disordered domains. The effects of fusion peptides, such as from hemagglutinin of influenza virus (wt20), and curvature- inducing proteins on membrane ordering will be studied to test the hypotheses that increased bilayer ordering is associated with more robust membrane fusion and that membrane curvature-inducing proteins will induce changes in the head group ordering of negatively charged lipids, based on the observation that wt20 increases the ordering of the lipid headgroups. By means of the powerful pulsed-dipolar ESR spectroscopy (PDS) cultivated by the Freed group for studying membrane protein structure and aggregation, the aggregation number and structural changes of spin-labeled wt20 peptide as a function of wt20 concentration will be determined, such as structural changes will be correlated with the changes in lipid ordering profile in the membrane. By means of multi-frequency ESR and PDS, the effects of hydrophobic mismatch between peptide length and lipid bilayer thickness, such as tilting of trans-membrane helices and peptide aggregation, will be studied for synthetic WALP and KALP peptides, based on previously developed methods and results. Additional studies by PDS will be directed to the determination of structures of large membrane proteins and their complexes. This includes spin-labeled BAR domain-containing proteins to determine the conformational changes that occur upon membrane binding. A second study is that of membrane-bound conformations of human synucleins including their Parkinson's disease (PD) linked-mutants to test our hypothesis that alpha- synuclein (aS) may exist in vivo in both extended helix and U-shaped form, each of which have already been demonstrated in model systems. A third study is to determine the structure of intact chemoreceptors and the conformational changes they undergo upon activation. The focus will be on the complex that the four protein unit, CheA/CheW, forms with the receptor. 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, an neurological disorders (including PD).

Public Health Relevance

We are studying structures of proteins and cell membranes, as well as the way proteins interact with other components of cell membranes, such as lipids and cholesterols. Our study will focus on understanding mechanisms by which cells communicate with each other through exchange of cellular components. Disorder in the structure of the proteins and the manner of cell communication may lead to allergic conditions, arteriosclerosis, Parkinson's and other diseases.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-B (02))
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Sastre, Antonio
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Cornell University
Schools of Arts and Sciences
United States
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Lai, Alex L; Millet, Jean K; Daniel, Susan et al. (2017) The SARS-CoV Fusion Peptide Forms an Extended Bipartite Fusion Platform that Perturbs Membrane Order in a Calcium-Dependent Manner. J Mol Biol 429:3875-3892
Snead, David; Lai, Alex L; Wragg, Rachel T et al. (2017) Unique Structural Features of Membrane-Bound C-Terminal Domain Motifs Modulate Complexin Inhibitory Function. Front Mol Neurosci 10:154
Pinello, Jennifer Fricke; Lai, Alex L; Millet, Jean K et al. (2017) Structure-Function Studies Link Class II Viral Fusogens with the Ancestral Gamete Fusion Protein HAP2. Curr Biol 27:651-660
Sukomon, Nattakan; Widom, Joanne; Borbat, Peter P et al. (2017) Stability and Conformation of a Chemoreceptor HAMP Domain Chimera Correlates with Signaling Properties. Biophys J 112:1383-1395
Lai, Alex L; Clerico, Eugenia M; Blackburn, Mandy E et al. (2017) Key features of an Hsp70 chaperone allosteric landscape revealed by ion-mobility native mass spectrometry and double electron-electron resonance. J Biol Chem 292:8773-8785
Samanta, Dipanjan; Widom, Joanne; Borbat, Peter P et al. (2016) Bacterial Energy Sensor Aer Modulates the Activity of the Chemotaxis Kinase CheA Based on the Redox State of the Flavin Cofactor. J Biol Chem 291:25809-25814
Georgieva, Elka R; Borbat, Peter P; Grushin, Kirill et al. (2016) Conformational Response of Influenza A M2 Transmembrane Domain to Amantadine Drug Binding at Low pH (pH 5.5). Front Physiol 7:317
Georgieva, Elka R; Borbat, Peter P; Norman, Haley D et al. (2015) Mechanism of influenza A M2 transmembrane domain assembly in lipid membranes. Sci Rep 5:11757
Tang, Shaogeng; Henne, W Mike; Borbat, Peter P et al. (2015) Structural basis for activation, assembly and membrane binding of ESCRT-III Snf7 filaments. Elife 4:
Franck, John M; Chandrasekaran, Siddarth; Dzikovski, Boris et al. (2015) Focus: Two-dimensional electron-electron double resonance and molecular motions: The challenge of higher frequencies. J Chem Phys 142:212302

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