Decoding PIP signaling: structure and catalytic mechanisms of the human phosphoinositide 5-phosphatases.

Phosphoinositides (PIPs) are low-abundance membrane lipids that define organelle identity and regulate intracellular signaling and membrane trafficking events. Their functional diversity arises from reversible phosphorylation of the inositol ring, generating distinct lipid species that act as spatial and temporal signaling cues within cellular membranes. The interconversion of these PIP species is tightly controlled by lipid kinases and phosphatases. Among these, phosphoinositide 5-phosphatases (5-PPases) selectively remove the 5-phosphate from phosphoinositides and soluble inositol phosphates, thereby controlling the composition and turnover of PIP species. Following an overview of general phosphoinositide metabolism, including a brief description of phosphoinositide kinases and 3-, 4-, and Sac-phosphatases, we discuss in detail the domain organization, substrate specificity, and physiological roles of the 10 mammalian 5-PPases. We specifically focus on recent structural studies that reveal how a conserved catalytic domain is combined with additional domains that control enzyme localization, protein-protein interactions and regulation. High-resolution structures of enzyme-substrate and enzyme-product complexes provide insight into phosphoinositide recognition, catalytic mechanisms, and allosteric regulation. In line with their wide variety of cellular functions, dysregulation of 5-PPases is linked to numerous diseases, including neurodegeneration, metabolic disorders, ciliopathies, and cancer. Despite recent progress, key questions remain, including their regulation and membrane-dependent activity within cells. Further developments are required to advance both our fundamental understanding and therapeutic development.