Fig. 6.

Signal integration in modular signaling proteins. PPHK features a typical “beans-on-the-stalk” architecture, where the sensor (input) and effector (output) domains are attached to a helical spine, where long linker helices (cylinders) are tethered at the dimer interface. The helical tethering may result in 2 kinds of asymmetry (marked by double-headed arrows): the dimer asymmetry across the dimer interface and the state asymmetry (the R vs. T state) between the adjacent domains. The sensor and effector domains are often separated by lipid bilayers in transmembrane receptors that share similar architectures. The purple arrow and red 3-way arrows represent the “molecular levers” in PPHK that facilitate the signal coupling from each sensory site to the helical spine, where global structural changes are reconciled via concerted helical bending, unwinding, and/or compression. The helical spine thus functions as a signaling hub, where various input signals are integrated to affect the same effector domain in the same protein framework. HK, histidine kinase; P, phosphorylation signal.