Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders

Biochemistry. 2015 Feb 24;54(7):1576-82. doi: 10.1021/acs.biochem.5b00028. Epub 2015 Feb 13.


Phosphoinositides are membrane components that play critical regulatory roles in mammalian cells. The enzyme PTEN, which catalyzes the dephosphorylation of the phosphoinositide PIP3, is damaged in most sporadic tumors. Mutations in the PTEN gene have also been linked to autism spectrum disorders and other forms of delayed development. Here, human PTEN is shown to be on the cusp of unfolding under physiological conditions. Variants of human PTEN linked to somatic cancers and disorders on the autism spectrum are shown to be impaired in their conformational stability, catalytic activity, or both. Those variants linked only to autism have activity higher than the activity of those linked to cancers. PTEN-L, which is a secreted trans-active isoform, has conformational stability greater than that of the wild-type enzyme. These data indicate that PTEN is a fragile enzyme cast in a crucial role in cellular metabolism and suggest that PTEN-L is a repository for a critical catalytic activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Autistic Disorder / genetics*
  • Autistic Disorder / metabolism
  • Genetic Variation*
  • Humans
  • Models, Molecular
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • PTEN Phosphohydrolase / chemistry*
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism
  • Protein Conformation
  • Protein Stability
  • Protein Unfolding


  • PTEN Phosphohydrolase
  • PTEN protein, human