BPS2026 - Membrane-regulated oligomerization of SHIP2 revealed by cryoEM

Src homology 2 domain-containing inositol-5 phosphatase 2 (SHIP2) is a lipid phosphatase that shapes PI3K/AKT signaling by dephosphorylating PIP3, thereby regulating cell proliferation, adhesion, and survival. Aberrant SHIP2 activity has been linked to cancer, type 2 diabetes, and neurodegeneration, yet its regulatory mechanisms at the membrane have remained elusive. We used cryogenic electron microscopy to determine the structure of the SHIP2 pleckstrin-homology-related (PHR), phosphatase, and C2 domains. The PHR domain engages the catalytic and C2 domains to align lipid-binding surfaces into a planar arrangement that enhances membrane avidity. On PIP3-containing monolayers, SHIP2 assembles into higher-order oligomers stabilized by interdomain interactions between neighboring molecules. This oligomerization was recapitulated in solution by PI(3,4)P2 binding, indicating that lipid composition governs SHIP2 recruitment and cooperative enzymatic activation. These results reveal a structural mechanism by which SHIP2 integrates membrane lipid cues to regulate phosphoinositide metabolism, offering new insight into how lipid environment modulates receptor-proximal signaling pathways.