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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\u2010related 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\u2010bearing model membranes is 5.6\u2010fold enhanced in comparison to wild\u2010type PTEN. In contrast, we find that binding to phosphatidylinositol\u20104,5\u2010bisphosphate (PI(4,5)P<jats:sub>2<\/jats:sub>) model membranes is 2.5\u2010fold decreased for the mutant PTEN in comparison to wild\u2010type PTEN. The structural change previously found for wild\u2010type PTEN upon interaction with PI(4,5)P<jats:sub>2<\/jats:sub>, is absent for H93R PTEN. Consistent with the increased binding to phosphatidylserine, we find enhanced plasma membrane association of PTEN\u2010GFP in U87MG cells. However, this enhanced plasma membrane association does not translate into increased PI(3,4,5)P<jats:sub>3<\/jats:sub> turnover, since <jats:italic>in vivo<\/jats:italic> studies show a reduced activity of the H93R PTEN\u2010GFP mutant. Because the interaction of PI(4,5)P<jats:sub>2<\/jats:sub> with PTEN's N\u2010terminal domain is diminished by this mutation, we hypothesize that the interaction of PTEN's N\u2010terminal domain with the phosphatase domain is impacted by the H93R mutation, preventing PI(4,5)P<jats:sub>2<\/jats:sub> from inducing the conformational change that activates phosphatase activity.<\/jats:p>","DOI":"10.1002\/pro.483","type":"journal-article","created":{"date-parts":[[2010,8,17]],"date-time":"2010-08-17T19:22:20Z","timestamp":1282072940000},"page":"1948-1956","source":"Crossref","is-referenced-by-count":35,"title":["A mutant form of PTEN linked to autism"],"prefix":"10.1002","volume":"19","author":[{"given":"Roberta 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