Featured System - May 2015
Short description: DivL shares many structural features with other bacterial signaling proteins, but has been modified by evolution to reverse the typical directionality of signaling.
Cells are wired with a complex network of sensors and signaling devices, which together respond to changes in the environment. The networks in and between our cells are very complex, but bacteria often take simpler approaches. For instance, many bacteria employ linear signal transducers called two-component systems. As the name implies, these are composed of two proteins: a membrane-bound sensor and a response regulator protein. When the sensor receives its environmental signal, it phosphorylates the response regulator, which then alters the expression of target genes appropriately.
Biology often finds ways to evolve new tools from its existing toolbox of molecules. PSI researchers at JCSG have found that Caulobacter bacteria use a similar two-component system when they are making decisions about how to divide, but it is wired in reverse. These bacteria divide to form two different cell types--a swarmer and a stalked cell. A collection of proteins localized at each pole of the dividing cell decide which half will be which. The DivL protein then delivers these instructions to the appropriate machinery for changing gene expression. DivL is very similar to the sensor protein in two-component systems, but instead of delivering a signal to a response regulator, it receives a signal from one.
DivL is a large, dimeric protein with several moving parts. The signal transducing portion, shown here from PDB entry 4q20, takes input from proteins at the two cellular poles and passes it on. This portion is connected to three PAS domains (shown schematically here), and the whole thing is connected to the membrane by a short transmembrane segment. Typical two component sensors also include a large sensor domain outside the cell, which is not found in DivL.
Several structures of two-component systems have revealed how the sensor protein interacts with the response regulator. The structure shown here (PDB entry 3a0r) includes the histidine kinase domain of the sensor protein (in blue) with one PAS domain. The RR protein (shown here in green) binds in a pocket on the side of the sensor protein, close to a histidine that carries a phosphate. This phosphate is transferred to the response regulator to activate it. In DivL, this histidine is changed to a tyrosine, which does not get phosphorylated. However, it guides a change in conformation that performs the DivL signaling task.
DivL includes the two signature alpha helices of two-component sensors, which are at the center of signal transfer. A proline forms a kink in the center of the "input" helix, allowing interactions of DivL with is partners to bend this helix back and forth. Motions of tyrosine 550 are are thought to play a key role in these interactions. The conformational change is then propagated to the "output" helix and finally to the CA domain, which passes the signal on. The dimeric complex of DivL is asymmetric, showing some of the flexibility involved in the signal transfer. The two subunits are overlapped here to show the differences. To explore this structure in more detail, the JSmol tab below displays an interactive JSmol image.
The two subunits of the DivL structure are superimposed to show differences in the two conformations. A proline (magenta) forms a kink in the long input helix, and a tyrosine (red) is thought to be important in conformational changes linked to signaling. Use the buttons to toggle between the two conformations and to change the representation.
4q20: Childers W. S. et al. Cell fate regulation governed by a repurposed bacterial histidine kinase. PLoS Biology 12, e1001979 (2014).
Casino, P., Rubio, V. & Marina, A. The mechanism of signal transduction by two- component systems. Curr. Op. Struct. Biol. 20, 763-771 (2010).
3a0r: Yamada, S. et al. Structure of PAS-linked histidine kinase and the response regulator complex. Structure 17, 1333-1344 (2009).