title: The PTEN Tumor Suppressor Forms Homodimers in Solution.
abstract: As the phosphoinositol-3-kinase antagonist in the PI3K pathway, the PTEN tumor suppressor exerts phosphatase activity on diacylphosphatidylinositol triphosphate in the plasma membrane. Even partial loss of this activity enhances tumorigenesis, but a mechanistic basis for this aspect of PTEN physiology has not yet been established. It was recently proposed that PTEN mutations have dominant-negative effects in cancer via PTEN dimers. We show that PTEN forms homodimers in vitro, and determine a structural model of the complex from SAXS and Rosetta docking studies. Our findings shed new light on the cellular control mechanism of PTEN activity. Phosphorylation of the unstructured C-terminal tail of PTEN reduces PTEN activity, and this result was interpreted as a blockage of the PTEN membrane binding interface through this tail. The results presented here instead suggest that the C-terminal tail functions in stabilizing the homodimer, and that tail phosphorylation interferes with this stabilization.
authors: Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA; NIST Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA.
authors: Frank
authors: F
authors: Heinrich
authors: BioCAT, Center for Synchrotron Radiation Research and Instrumentation, Argonne National Laboratory, Argonne, IL 60439, USA; Department of Biological and Chemical Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA.
authors: Srinivas
authors: S
authors: Chakravarthy
authors: Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA; NIST Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA.
authors: Hirsh
authors: H
authors: Nanda
authors: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC 3800, Australia; Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Antonella
authors: A
authors: Papa
authors: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Pier Paolo
authors: PP
authors: Pandolfi
authors: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors: Alonzo H
authors: AH
authors: Ross
authors: Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA 01609, USA.
authors: Rakesh K
authors: RK
authors: Harishchandra
authors: Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA 01609, USA.
authors: Arne
authors: A
authors: Gericke
authors: Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA; NIST Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA. Electronic address: quench@cmu.edu.
authors: Mathias
authors: M
authors: Lösche
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D062105:Molecular Docking Simulation; D051059:PTEN Phosphohydrolase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction
chemical_list: D018129:Phosphatidylinositol Phosphates; D011994:Recombinant Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PI3K/Akt pathway; PTEN phosphatase; SAXS; dimer structure; protein docking