John, L.H.; Naughton, F.B.; Sansom, M.S.P.; Larsen, A.H. The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2. Membranes2023, 13, 408.
John, L.H.; Naughton, F.B.; Sansom, M.S.P.; Larsen, A.H. The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2. Membranes 2023, 13, 408.
John, L.H.; Naughton, F.B.; Sansom, M.S.P.; Larsen, A.H. The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2. Membranes2023, 13, 408.
John, L.H.; Naughton, F.B.; Sansom, M.S.P.; Larsen, A.H. The Role of C2 Domains in Two Different Phosphatases: PTEN and SHIP2. Membranes 2023, 13, 408.
Abstract
Phosphatase and tensin homologue (PTEN) and SH2-containing-inositol-5’-phosphatase 2 (SHIP2) are structurally and functionally similar. They both consist of a Phosphastase (Ptase) domain and an adjacent C2 domain, and both proteins dephosphorylate phosphoinositol-tri(3,4,5)phosphate, PI(3,4,5)P3; 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.
Keywords
PTEN; SHIP2; C2 domain; Ptase domain; MD
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
