title: Defining the membrane-associated state of the PTEN tumor suppressor protein.
abstract: Phosphatase and tensin-homolog deleted on chromosome 10 (PTEN) is a tumor-suppressor protein that regulates phosphatidylinositol 3-kinase (PI3-K) signaling by binding to the plasma membrane and hydrolyzing the 3' phosphate from phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) to form phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2). Several loss-of-function mutations in PTEN that impair lipid phosphatase activity and membrane binding are oncogenic, leading to the development of a variety of cancers, but information about the membrane-associated state of PTEN remains sparse. We have modeled a membrane-associated state of the truncated PTEN structure bound to PI(3,4,5)P3 via multiscale molecular dynamics simulations. We show that the location of the membrane-binding surface agrees with experimental observations and is robust to changes in lipid composition. The level of membrane interaction is substantially reduced in the phosphatase domain for the triple mutant R161E/K163E/K164E, in line with experimental results. We observe clustering of anionic lipids around the C2 domain in preference to the phosphatase domain, suggesting that the C2 domain is involved in nonspecific interactions with negatively charged lipid headgroups. Finally, our simulations suggest that the oncogenicity of the R335L mutation may be due to a reduction in the interaction of the mutant PTEN with anionic lipids.
authors: Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors: Craig N
authors: CN
authors: Lumb
authors: Mark S P
authors: MS
authors: Sansom
mesh_terms: D000595:Amino Acid Sequence; D000838:Anions / Q000737:chemistry; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D051059:PTEN Phosphohydrolase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010716:Phosphatidylinositols / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D000838:Anions; D008051:Lipid Bilayers; D010716:Phosphatidylinositols; C118303:phosphoinositide-3,4,5-triphosphate; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human