PTEN catalysis of phospholipid dephosphorylation reaction follows a two-step mechanism in which the conserved aspartate-92 does not function as the general acid — Mechanistic analysis of a familial Cowden disease-associated PTEN mutation
Autor: | Heung-Chin Cheng, Hong-Jian Zhu, Harshal Hanumant Nandurkar, Joel Yeong Chit Chia, Joanna E. Gajewski, Daisy Sio Seng Lio, Terrence D. Mulhern, Yi Xiao |
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Rok vydání: | 2007 |
Předmět: |
Time Factors
Glycine Protein tyrosine phosphatase medicine.disease_cause Models Biological Catalysis Conserved sequence Dephosphorylation Phosphatidylinositol Phosphates Phosphoprotein Phosphatases medicine Animals Humans PTEN Cysteine Phosphorylation Conserved Sequence Phospholipids Aspartic Acid Mutation Binding Sites biology Hydrolysis Phosphatidylethanolamines PTEN Phosphohydrolase Active site Cell Biology Hydrogen-Ion Concentration Rats Kinetics Biochemistry Phospholipid dephosphorylation biology.protein Hamartoma Syndrome Multiple Phosphorus Radioisotopes |
Zdroj: | Cellular Signalling. 19:1434-1445 |
ISSN: | 0898-6568 |
Popis: | PTEN exerts its tumour suppressor function by dephosphorylating the phospholipid second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP(3)). Herein, we demonstrate that the PTEN-catalysed PIP(3) dephosphorylation reaction involves two-steps: (i) formation of a phosphoenzyme intermediate (PE) in which Cys-124 in the active site is thiophosphorylated, and (ii) hydrolysis of PE. For protein tyrosine- and dual-specificity phosphatases, catalysis requires the participation of a conserved active site aspartate as the general acid in Step 1. Its mutation to alanine severely limits PE formation. However, mutation of the homologous Asp-92 in PTEN does not significantly limit PE formation, indicating that Asp-92 does not act as the general acid. G129E is a common germline PTEN mutations found in Cowden syndrome patients. Mechanistic analysis reveals that this mutation inactivates PTEN by both significantly slowing down Step 1 and abolishing the ability to catalyse Step 2. Taken together, our results highlight the mechanistic similarities and differences between PTEN and the conventional protein phosphatases and reveal how a disease-associated mutation inactivates PTEN. |
Databáze: | OpenAIRE |
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