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: Frank Heinrich, Srinivas Chakravarthy, Hirsh Nanda, Antonella Papa, Pier Paolo Pandolfi, Alonzo H Ross, Rakesh K Harishchandra, Arne Gericke, Mathias Lösche
• Journal: Structure (London, England : 1993) (Structure) Vol. 23 Issue 10 Pg. 1952-1957 (Oct 06 2015) ISSN: 1878-4186 [Electronic] United States
• PMID: 26299948 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Phosphatidylinositol Phosphates
• Recombinant Proteins
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Binding Sites
• Cell Line
• Cell Membrane (chemistry)
• Crystallography, X-Ray
• Escherichia coli (genetics, metabolism)
• Gene Expression
• Humans
• Molecular Docking Simulation
• PTEN Phosphohydrolase (chemistry, genetics, metabolism)
• Phosphatidylinositol Phosphates (chemistry, metabolism)
• Phosphorylation
• Protein Binding
• Protein Folding
• Protein Interaction Domains and Motifs
• Protein Multimerization
• Protein Structure, Secondary
• Recombinant Proteins (chemistry, genetics, metabolism)
• Scattering, Small Angle
• X-Ray Diffraction