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

Abstract

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)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.

Regulatory mechanisms triggered by enzyme interactions with lipid membrane surfaces

“…More recent MD simulations ( John et al, 2023 ) with SHIP2 bound to a lipid membrane suggest that C2 causes conformational changes in L4 and α5–7, but there is no change in flexibility in these regions, which may be because that the presence of a lipid membrane changes protein conformational dynamics. Another study ( Le Coq et al, 2021 ) focusing on the function of the PHR domain of SHIP2 showed that the reaction product PI(3,4)P 2 induces higher activity of PHR-Ptase-C2 compared to Ptase-C2 and Ptase.…”

“…A simulation and calculation work also compared the role of C2 domains in PTEN and SHIP2 ( John et al, 2023 ). This study showed that the C2 domain of PTEN plays an important role in membrane binding and adjusts the posture of PTEN for substrate binding which is similar to the role of other C2 domains.…”