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<su...
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MDPI AG
2023-04-01
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Series: | Membranes |
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Online Access: | https://www.mdpi.com/2077-0375/13/4/408 |
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author | Laura H. John Fiona B. Naughton Mark S. P. Sansom Andreas Haahr Larsen |
author_facet | Laura H. John Fiona B. Naughton Mark S. P. Sansom Andreas Haahr Larsen |
author_sort | Laura H. John |
collection | DOAJ |
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<sub>3</sub>; 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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institution | Directory Open Access Journal |
issn | 2077-0375 |
language | English |
last_indexed | 2024-03-11T04:45:44Z |
publishDate | 2023-04-01 |
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series | Membranes |
spelling | doaj.art-7e486fbd4b134956a901e7f5a730df6d2023-11-17T20:23:10ZengMDPI AGMembranes2077-03752023-04-0113440810.3390/membranes13040408The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2Laura H. John0Fiona B. Naughton1Mark S. P. Sansom2Andreas Haahr Larsen3Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UKDepartment of Biochemistry, University of Oxford, Oxford OX1 3QU, UKDepartment of Biochemistry, University of Oxford, Oxford OX1 3QU, UKDepartment of Biochemistry, University of Oxford, Oxford OX1 3QU, UKPhosphatase 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<sub>3</sub>; 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.https://www.mdpi.com/2077-0375/13/4/408PTENSHIP2phosphoinositolPIPMDC2 domain |
spellingShingle | Laura H. John Fiona B. Naughton Mark S. P. Sansom Andreas Haahr Larsen The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2 Membranes PTEN SHIP2 phosphoinositol PIP MD C2 domain |
title | The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2 |
title_full | The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2 |
title_fullStr | The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2 |
title_full_unstemmed | The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2 |
title_short | The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2 |
title_sort | role of c2 domains in two different phosphatases pten and ship2 |
topic | PTEN SHIP2 phosphoinositol PIP MD C2 domain |
url | https://www.mdpi.com/2077-0375/13/4/408 |
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