Figure 10.

A model for ligand binding to WW1-WW2 tandem module of WWOX. In the unliganded state, the WW1-WW2 tandem module is proposed to exist in an equilibrium exchange between a closed state and an open state. In the closed state, the physical association between the WW domains prevents ligand binding. In the open state, the WW domains are no longer physically associated but may still be somewhat spatially oriented so as to allow unhindered access to the ligand. In the absence of PPXY ligand, the equilibrium between the open and the closed state predominantly lies in favor of the latter. Subsequent binding of PPXY ligand to WW1 domain within the open state shifts the equilibrium in its direction by virtue of the ability of WW1-WW2 tandem module to undergo a conformational switch so as to displace the WW2 lid.