SH2 containing inositol phosphatase 2 (SHIP2) removes the 5-phosphate from PIP3 and thereby, like PTEN, negatively regulate PIP3 levels in the plasma membrane. Despite their importance little is known about mechanisms of SHIP regulation. We solved a crystal structure containing the catalytic and C2 domains of SHIP2, which together with extensive biochemistry and cell biology showed how the C2 domain induces catalytic activation of SHIP2 (Figure). Currently, we study the role of the PH domain flanking the catalytic domain. We find that the domain binds the PIP3 substrate and PIP2 product and this binding allosterically further activates SHIP. Together, this shows how the C2 and PH domains concertedly act to recruit SHIP to PIP3 rich membranes to adopt a highly active state.

Allosteric signalling in SHIP2 on the membrane
(A) The C2 boosts catalytic activity in SHIP2: i) by binding to PtdSer membrane lipids and positioning the active site for efficient PIP3 attack and ii) providing allosteric signals (“H-path”/“P-path”) to affect binding to hydrophobic or polar regions in PIP3. (B) Activity assays show that the C2 domain and PtdSer enhance SHIP2 activity for PIP3 in membranes.