Molecular modeling of the bacterial chemotaxis receptors Tar and Trg

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Molecular modeling of the bacterial chemotaxis receptors Tar and Trg

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Title: Molecular modeling of the bacterial chemotaxis receptors Tar and Trg
Author: Peach, Megan L
Abstract: Bacterial chemotaxis receptors signal across the membrane by a conformational change that traverses their periplasmic, transmembrane, and cytoplasmic domains. The mechanism of this conformational change is controversial and is not completely understood. Molecular models of the periplasmic and transmembrane domains of the homodimeric chemotaxis receptors Trg and Tar were constructed, using the coordinates of an unrelated four-helix coiled coil as a template and the X-ray structure of the periplasmic domain of Tar to establish register and positioning. The models were tested and refined using the extensive experimental data for cross-linking propensities between cysteines introduced into adjacent transmembrane helices.These refined models were used to assess the effects of inter-helical disulfides, using a measure of disulfide potential energy, on two previously proposed mechanisms for ligand-induced conformational changes in the receptor structure: an axial sliding motion of one helix in a subunit, and a rotational motion between the two subunits in the dimer. These proposed mechanisms were tested further, along with the theory that receptor signaling might involve a change in dynamics, using molecular dynamics simulations of the fully solvated periplasmic and transmembrane domains.Testing of disulfide effects on receptor motion showed that a sliding motion of transmembrane helix 2 is consistent with experimental data on receptor signaling. However, inter-helical disulfides would not significantly constrain an inter-subunit rotational motion. The molecular dynamics simulations showed that the transmembrane domain has a high degree of dynamic flexibility, and that in the isolated periplasmic domain ligand binding induces an inter-subunit rotation that is of much greater magnitude than was previously concluded from analysis of the periplasmic domain crystal structures.These results suggest a new model for transmembrane signaling in which an intersubunit rotational motion is converted into a helical sliding motion via a flexible transmembrane domain and linker region. Thus, both proposed mechanisms occur and have functional roles.
Description: Thesis (Ph. D.)--University of Washington, 2001
URI: http://hdl.handle.net/1773/8123

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