The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2

Phosphatase and tensin homologue (PTEN) and SH2-containing inositol 5'-phosphatase 2 (SHIP2) are structurally and functionally similar. They both consist of a phosphatase (Ptase) domain and an adjacent C2 domain, and both proteins dephosphorylate phosphoinositol-tri(3,4,5)phosphate, PI(3,4,5)P...

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Published in:Membranes (Basel) 2023-04, Vol.13 (4), p.408
Main Authors: John, Laura H, Naughton, Fiona B, Sansom, Mark S P, Larsen, Andreas Haahr
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Algorithms
Allosteric properties
Binding
C2 domain
Catalytic activity
Conformation
Crystal structure
Free energy
Inositol
Inositol polyphosphate 5-phosphatase
Inositols
Lipids
Membranes
Molecular dynamics
Phosphatase
Phosphatases
Phosphatidylinositol 3,4,5-triphosphate
phosphoinositol
PIP
Proteins
PTEN
PTEN protein
SHIP2
Simulation
Surface active agents
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description Phosphatase and tensin homologue (PTEN) and SH2-containing inositol 5'-phosphatase 2 (SHIP2) are structurally and functionally similar. They both consist of a phosphatase (Ptase) domain and an adjacent C2 domain, and both proteins dephosphorylate phosphoinositol-tri(3,4,5)phosphate, PI(3,4,5)P ; PTEN at the 3-phophate and SHIP2 at the 5-phosphate. Therefore, they play pivotal roles in the PI3K/Akt pathway. Here, we investigate the role of the C2 domain in membrane interactions of PTEN and SHIP2, using molecular dynamics simulations and free energy calculations. It is generally accepted that for PTEN, the C2 domain interacts strongly with anionic lipids and therefore significantly contributes to membrane recruitment. In contrast, for the C2 domain in SHIP2, we previously found much weaker binding affinity for anionic membranes. Our simulations confirm the membrane anchor role of the C2 domain in PTEN, as well as its necessity for the Ptase domain in gaining its productive membrane-binding conformation. In contrast, we identified that the C2 domain in SHIP2 undertakes neither of these roles, which are generally proposed for C2 domains. Our data support a model in which the main role of the C2 domain in SHIP2 is to introduce allosteric interdomain changes that enhance catalytic activity of the Ptase domain.
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subjects 1-Phosphatidylinositol 3-kinase
AKT protein
Algorithms
Allosteric properties
Binding
C2 domain
Catalytic activity
Conformation
Crystal structure
Free energy
Inositol
Inositol polyphosphate 5-phosphatase
Inositols
Lipids
Membranes
Molecular dynamics
Phosphatase
Phosphatases
Phosphatidylinositol 3,4,5-triphosphate
phosphoinositol
PIP
Proteins
PTEN
PTEN protein
SHIP2
Simulation
Surface active agents
title The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2
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