Image credit: Analogicus (CC0)
Inside a cell, many different signals carry information that is essential for the cell to remain healthy and perform its role in the body. It is, therefore, very important that the signals are sent to the right places at the right times. Scaffold proteins play an essential role in organizing these signals by bringing specific proteins and other molecules into close contact at particular times and locations within the cell. Defects in scaffolding proteins can lead to cancer, psychiatric disorders and other diseases, so these proteins represent potential new targets for medicinal drugs.
Many scaffolding proteins assemble groups of proteins on the surface of the membrane that surrounds the cell. Previous studies have shown that scaffolding proteins are able to bind to several other proteins as well as the membrane itself at the same time. However, the precise way in which scaffolding proteins assemble such groups is not clear because it is technically challenging to study this process in living cells. To overcome this challenge, Erlendsson, Thorsen et al. used a new experimental setup known as supported cell membrane sheets – which provides direct access to the side of the cell membrane that usually faces into the cell – to study two scaffolding proteins known as PICK1 and PSD-95.
The experiments show that PICK1 and PSD-95 bind to their partner proteins up to 100 times more strongly than previously observed using other approaches. This is due to the scaffolding proteins binding more strongly to both their partners and the membrane.
Unexpectedly, the experiments show that the shape and physical characteristics of the partner protein have no effect on the increase in the strength of the binding. Further experiments suggest that altering the ability of the PDZ domain of PICK1 to bind to partner proteins changes the mode of action of the PICK1 protein so that it can activate different responses in the cell. Together these findings imply that the ability of scaffolding proteins to bind to their partner proteins is finely tuned to encode specific responses in cells in different situations – a hypothesis that Erlendsson, Thorsen et al. are planning to test in intact cells.
