Phosphoinositides and inositol phosphates as molecular glues

Inositol phosphates (IPs) and phosphoinositide lipids (PIPs) are regulatory molecules critical for a wide array of functions in eukaryotic cells. Membrane PIPs have clear functions in transient recruitment of signaling proteins to membranes, and IPs have been found locked in the core of proteins as structural cofactors. However, several recent studies have suggested IPs and PIPs can mediate protein-protein interactions at the interface between proteins, functioning as natural molecular glues. Here, we present recent structural biology describing how IPs and PIPs mediate these regulatory responses at protein interfaces. In addition, we describe protein-protein interactions mediated by IPs and PIPs, for which evidence supporting a natural molecular glue role is unclear or awaits further high-resolution structural analyses. Together, we put forth that PIPs and IPs have a historically under-appreciated role at protein-protein interfaces, requiring a more systematic, structural approach to elucidate.