Control of Membrane Protein Structure and Function by Sequence and Lipid

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Intellectual MeritProteins embedded in the lipid membranes that surround cells control the interaction of cells with their environment. They transport molecules in and out of cells and transmit messages between the external environment and the interior of the cell. However, there is much that is not known about how membrane protein structure allows them to carry out these functions. A key to answer this question is to understand the behavior of transmembrane (TM) helices, the predominant structure found in the membrane-embedded portion of membrane proteins. TM helices are helical sequences of amino acids that cross from one side of the membrane to the other. The goal of this proposal is to determine how the amino acid sequence of TM helices and the chemical composition of the lipids in a membrane control the ability of TM helices to interconvert between different structural and functional states. In particular, how amino acid sequence and lipid composition affect the position of a TM helix in membranes, and how TM helix position within the membrane alters function will be examined. To do this, the project will define amino acid mutations of TM helices that alter the position of TM helices within a membrane in a controllable fashion. Fluorescence methods, developed in previous studies, will then be used to measure the position of TM helices in a membrane. The behavior of artificial TM helices, in which carefully controlled sequences can answer precise questions concerning the sequence/structure relationship, will be studied in artificial lipid membranes in which lipid composition and other environmental conditions can be varied. In addition, TM helices with the amino acid sequences found in natural membrane proteins will be studied, in conjunction with the corresponding intact membrane proteins, in order to demonstrate how the knowledge gained can be used to define the relationship between TM helix positioning and function. Broader ImpactThis project will have a broad impact on career development of future scientists, including minority students, at the educational level by training both graduate and undergraduate students (including via contacts with other local institutions) in the conduct of research, fluorescence principles, and membrane structure and function. Training in the unique fluorescence quenching approaches used in the lab would aid dissemination of these techniques by these students after they graduate and apply them in their future careers. By defining strategies other labs can use to approach the relationship of membrane protein helix structure to function there would also be a broad impact upon bioremediation of toxic compounds by plants and bacteria (which involves membrane protein transporters), biomaterials applications (in which membrane proteins are being studied as hypersensitive biosensors) and bioelectronics applications.