It takes two to tango: The second membrane-binding site in peripheral proteins.

In this issue of Structure, Soteriou et al. use cell biology, in vitro reconstitution approaches, and molecular dynamics (MD) simulations to characterize the membrane association of AKT1. The authors show that the AKT1 pleckstrin homology domain contains two essential and cooperative PI(3,4,5)P-binding sites that enable stable membrane binding of AKT1 in the requisite orientation required for effective downstream signaling.