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
|