A mutant form of PTEN linked to autism

Protein Sci. 2010 Oct;19(10):1948-56. doi: 10.1002/pro.483.


The tumor suppressor, phosphatase, and tensin homologue deleted on chromosome 10 (PTEN), is a phosphoinositide (PI) phosphatase specific for the 3-position of the inositol ring. PTEN has been implicated in autism for a subset of patients with macrocephaly. Various studies identified patients in this subclass with one normal and one mutated PTEN gene. We characterize the binding, structural properties, activity, and subcellular localization of one of these autism-related mutants, H93R PTEN. Even though this mutation is located at the phosphatase active site, we find that it affects the functions of neighboring domains. H93R PTEN binding to phosphatidylserine-bearing model membranes is 5.6-fold enhanced in comparison to wild-type PTEN. In contrast, we find that binding to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P(2)) model membranes is 2.5-fold decreased for the mutant PTEN in comparison to wild-type PTEN. The structural change previously found for wild-type PTEN upon interaction with PI(4,5)P(2), is absent for H93R PTEN. Consistent with the increased binding to phosphatidylserine, we find enhanced plasma membrane association of PTEN-GFP in U87MG cells. However, this enhanced plasma membrane association does not translate into increased PI(3,4,5)P(3) turnover, since in vivo studies show a reduced activity of the H93R PTEN-GFP mutant. Because the interaction of PI(4,5)P(2) with PTEN's N-terminal domain is diminished by this mutation, we hypothesize that the interaction of PTEN's N-terminal domain with the phosphatase domain is impacted by the H93R mutation, preventing PI(4,5)P(2) from inducing the conformational change that activates phosphatase activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Autistic Disorder / enzymology
  • Autistic Disorder / genetics*
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Membrane Lipids / metabolism
  • Microscopy, Confocal
  • Mutation*
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phosphatidylinositols / metabolism
  • Phosphatidylserines / metabolism
  • Protein Binding
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Spectrophotometry, Infrared
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism


  • Membrane Lipids
  • Phosphatidylinositol 4,5-Diphosphate
  • Phosphatidylinositols
  • Phosphatidylserines
  • Recombinant Fusion Proteins
  • Tumor Suppressor Proteins
  • Green Fluorescent Proteins
  • PTEN Phosphohydrolase
  • PTEN protein, human