): All cell membranes are composed primarily of proteins and lipids. In the past few years it has become clear that the adsorption, insertion, conformation, and functioning of membrane proteins are all strongly influenced by the lipid bilayer matrix. Critical, unresolved questions in membrane biology concern how the compositional, structural, and mechanical properties of the bilayer modulate peptide binding and organization. Our overall goal is to determine how lipid-mediated forces affect selected interfacial, transmembrane, and acylated peptides and proteins of biological significance. We propose to relate the thermodynamics of peptide binding with specific structural and material properties of the bilayer by systematically varying the bilayer headgroup, hydrophobic thickness, compressibility modulus, and bending modulus. Our experiments will use a variety of biophysical techniques including isothermal titration calorimetry, X-ray diffraction, circular dichroism, fluorescence spectroscopy, and direct binding assays.
Our specific aims i nclude: (1) measuring the energetics of the steps in peptide partitioning into the bilayer, including peptide binding, insertion, and conformational changes, (2) determining the role of bilayer structure and material properties on peptide-lipid interactions, (3) testing current hypotheses concerning the formation, structure, and peptide binding properties of lipid domains (rafts), and (4) evaluating the hypothesis that proteins and peptides can be sorted in membranes on the basis of the length of their transmembrane hydrophobic domains or by protein palmitoylation. These fundamental experiments should yield data to quantitatively assess published theoretical treatments of the energetic components of peptide-lipid interactions, provide new information on the roles of the many classes of lipids found in biological membranes, and give insights on the mechanism of membrane localization of GAP-43, a protein critical to nerve growth and regeneration.
|McIntosh, Thomas J (2015) Stepping between membrane microdomains. Biophys J 108:783-784|
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|Zhang, Xiao-Xiang; McIntosh, Thomas J; Grinstaff, Mark W (2012) Functional lipids and lipoplexes for improved gene delivery. Biochimie 94:42-58|
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|Tong, Jihong; Briggs, Margaret M; McIntosh, Thomas J (2012) Water permeability of aquaporin-4 channel depends on bilayer composition, thickness, and elasticity. Biophys J 103:1899-908|
|Picazo-Juárez, Giovanni; Romero-Suárez, Silvina; Nieto-Posadas, Andrés et al. (2011) Identification of a binding motif in the S5 helix that confers cholesterol sensitivity to the TRPV1 ion channel. J Biol Chem 286:24966-76|
|Zhang, Xiao-Xiang; Prata, Carla A H; Berlin, Jason A et al. (2011) Synthesis, characterization, and in vitro transfection activity of charge-reversal amphiphiles for DNA delivery. Bioconjug Chem 22:690-9|
|Zhang, Xiao-Xiang; Prata, Carla A H; McIntosh, Thomas J et al. (2010) The effect of charge-reversal amphiphile spacer composition on DNA and siRNA delivery. Bioconjug Chem 21:988-93|
|Rosenbaum, Tamara; Simon, Sidney A; Islas, Leon D (2010) Ion channels in analgesia research. Methods Mol Biol 617:223-36|
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