Fig. 8. Helix-clutch model for transmembrane signaling by Tsr.
A portion of the TM2-control cable-AS1 segment in one Tsr subunit is pictured. Dark- or light-gray shaded segments are proposed to have α-helical secondary structure. Sidechains of control cable residues (only the I214 sidechain is shown) are proposed to interact with the membrane environment, but not with other residues in Tsr or in other proteins. A stable helical connection between TM2 and the AS1 helix of HAMP destabilizes packing of the HAMP bundle, favoring kinase-on output. The inward TM2 piston displacement (black triangle) promoted by binding of an attractant ligand to the periplasmic sensing domain perturbs the membrane environment of the I214 sidechain, creating a kink or break in helicity that alleviates the register mismatch between TM2 and AS1, thereby enhancing HAMP bundle packing to promote kinase-off output.