Structural investigation of inositol polyphosphate 4ˈ-phosphatase domain containing proteins INPP4B and P-Rex2

Phosphoinositides (PIs) are minor membrane lipids that act as key signalling molecules, with functions determined by phosphorylation of the inositol headgroup at the 3′, 4′, and 5′ positions. Their phosphorylation state is regulated by numerous kinases and phosphatases, including ~38 PI-phosphatases in humans grouped by positional specificity. While structures of several PI-phosphatase families are known, no active human 4′-PI-phosphatase structure had previously been solved. This thesis investigates two proteins containing the IP4P domain, INPP4B and P-Rex2. Cryo-EM analysis reveals the structure and catalytic mechanism of INPP4B, while structural studies of the proposed P-Rex2–PTEN complex indicate that their interaction and co-inhibition likely require additional cellular factors.