PTEN Requires a Stable Dimer Configuration to Effectively Suppress Tumor Growth

Molecular structural analysis has shown that the PTEN (phosphatase and tensin homolog) tumor suppressor can function effectively only when two wild-type alleles are present to form a stable dimer that can act on lipids in the cell membrane.

PTEN, which is missing in 60% to 70% of metastatic cancers in humans, is the name of a phospholipid phosphatase protein, and gene that encodes it. The PTEN gene acts as a tumor suppressor gene thanks to the role of its protein product in regulation of the cycle of cell division, preventing cells from growing and dividing too rapidly.

Due to difficulties in crystallizing the PTEN dimer, investigators at Carnegie Mellon University (Pittsburgh, PA, USA) and a group of international collaborators used an advanced small-angle X-ray scattering (SAXS) technique to establish its structure in aqueous solution.

They reported in the August 20, 2015, online edition of the journal Structure that PTEN formed homodimers in vitro. To be fully functional, the C-terminal tails of the two proteins comprising the PTEN dimers had to bind the protein bodies in a cross-wise fashion, which made them more stable. As a result, they could more efficiently interact with the cell membrane, regulate cell growth, and suppress tumor formation.

Phosphorylation of the unstructured C-terminal tail of PTEN reduced PTEN activity, and this result was interpreted as a blockage of the PTEN membrane binding interface through this tail. The results presented in this paper instead suggested that the C-terminal tail functioned in stabilizing the homodimer, and that tail phosphorylation interfered with this stabilization.

"Membrane-incorporated and membrane-associated proteins like PTEN make up one-third of all proteins in our body. Many important functions in health and disease depend on their proper functioning," said senior author Dr. Mathias Lösche, professor of physics and of biomedical engineering at Carnegie Mellon University. "Despite PTEN's importance in human physiology and disease, there is a critical lack of understanding of the complex mechanisms that govern its activity."

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