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

Sean B Johnston1, Ronald T Raines

  • 1Department of Biochemistry and ‡Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.

Biochemistry
|February 4, 2015
PubMed

Insights

The enzyme phosphatase and tensin homolog (PTEN) is crucial for cell regulation but is fragile. Cancer and autism-linked PTEN variants show reduced stability or activity, with autism variants being more active.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Metabolism

Background:

  • Phosphoinositides, like PIP3, are key membrane regulators in mammalian cells.
  • The enzyme PTEN dephosphorylates PIP3 and is frequently impaired in tumors and linked to developmental disorders.
  • PTEN's role in cellular metabolism and disease necessitates understanding its stability and function.

Purpose of the Study:

  • To investigate the conformational stability and catalytic activity of human PTEN.
  • To compare PTEN variants associated with cancer and autism spectrum disorders.
  • To characterize the properties of the PTEN-L isoform.

Main Methods:

  • Analysis of human PTEN conformational stability under physiological conditions.
  • Assessment of catalytic activity for wild-type and variant PTEN.
  • Comparison of PTEN and PTEN-L properties.

Main Results:

  • Human PTEN exists near its unfolding point under physiological conditions, indicating fragility.
  • PTEN variants linked to cancer and autism exhibit compromised conformational stability and/or catalytic activity.
  • PTEN variants associated solely with autism display higher catalytic activity than cancer-linked variants.
  • The secreted PTEN-L isoform demonstrates superior conformational stability compared to wild-type PTEN.

Conclusions:

  • PTEN is a fragile enzyme critical for cellular metabolism.
  • Impaired PTEN stability or activity contributes to cancer and developmental disorders.
  • PTEN-L represents a stable reservoir of PTEN's catalytic function.

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