J. Struct. Biol. 180, 394–408 (2012)

Credit: MATHIAS LÖSCHE

PTEN is a lipid phosphatase that hydrolyzes PtdIns(3,4,5)P3 to PtdIns(4,5)P2, and as such, it controls many cellular signaling events, including proliferation and apoptosis. PTEN localization to the inner leaflet of the plasma membrane is regulated by its own phosphorylation and through interaction with its substrate and anionic lipids such as phosphatidylserine. To examine the changes in PTEN conformation with binding to the membrane, Shenoy et al. performed neutron reflectometry experiments on full-length PTEN adsorbed to planar model membranes. Molecular dynamics simulations were used to corroborate the neutron reflectometry results and to refine the experimentally determined structure. On the bilayer, the structure of the PTEN core is flattened against the membrane surface as compared to the published crystal structure of a truncated PTEN and the PTEN solution structure. The data also suggest that PS localizes PTEN via the CBR3 motif of its C2 domain at the membrane surface while subsequent interaction with the PtdIns lipid locks it into place. Moreover, the study reveals that the disordered C-terminal tail is repelled from the bilayer interface by electrostatic interactions. In contrast, the tail wraps around the C2 domain in solution. This high-resolution look at the changes in PTEN structure and membrane properties suggest how zipper-forming salt bridges between the C terminus and the C2 domain regulate PTEN activity by controlling its access to the membrane.