Allostery is still a badly understood but very general mechanism in the protein world. In principle, an allosteric event occurs when a ligand (small or big) binds to a certain site of a protein and something (activity or function) changes at a different, distant site. A well-known example would be G-protein-coupled receptors that transport such an allosteric signal even across a membrane. But it does not have to be that far apart. As part of the Protein Folding and Dynamics series, I have recently watched a talk by Peter Hamm (Zurich) who presented work on an allosteric system that I thought was very interesting because it was small and most importantly, controllable.

PDZ domains are peptide-binding domains, often part of multi-domain proteins. For the work presented the researchers used the PDZ3 domain which is a bit special and has an additional (third) C-terminal α-helix (α3-helix) which is packing to the other side of the binding pocket. Previous work (Petit et al. 2009) had shown that removal of the α3-helix had changed ligand affinity but not PDZ structure, major changes were of an entropic nature instead. Peter Hamm’s group linked an azobenzene-derived photoswitch to that α3-helix; in its cis configuration stabilizing the α3-helix and destabilising in trans (see Figure 1).

What they found was that by switching from trans to cis, the helix was stabilized and the binding affinity for the ligand increased (up to 120-fold, temperature-dependent) at that distant site (hence an allosteric event). This allosteric communication also worked in the other direction as the rate of cis-to-trans isomerisation increased when the ligand was bound (compared to the native isomerisation rate without ligand). This combination of a small peptide-binding domain and a photoswitch constitutes a very small allosteric system (the smallest known today?) which states can be controlled by light and ligands. The size and controllability of this systems might open up more in-depth studies on how a (or at least this) allosteric signal is transmitted inside a protein.

They further determined binding enthalpies, the difference in driving force for cis-to-trans isomerisation and resulting from that, a force that is transmitted through the allosteric events and therefore termed ‘allosteric force’. For more details on their theoretical considerations for this as well as the experiments have a look at their paper: Sensing the allosteric force.