Crystal structure of the PTEN tumor suppressor: Implications for its phosphoinositide phosphatase activity and membrane association

The PTEN tumor suppressor is mutated in diverse human cancers and in heredi tary cancer predisposition syndromes. PTEN is a phosphatase that can act on both polypeptide and phosphoinositide substrates in vitro. The PTEN struct ure reveals a phosphatase domain that is similar to protein phosphatases bu t has an enlarged active site important for the accommodation of the phosph oinositide substrate. The structure also reveals that PTEN has a C2 domain. The PTEN C2 domain binds phospholipid membranes in vitro, and mutation of basic residues that could mediate this reduces PTEN's membrane affinity and its ability to suppress the growth of glioblastoma tumor cells. The phosph atase and C2 domains associate across an extensive interface, suggesting th at the C2 domain may serve to productively position the catalytic domain on the membrane.