Cellular and molecular interactions of phosphoinositides and peripheral proteins

Abstract

Anionic lipids act as signals for the recruitment of proteins containing cationic clusters to biological membranes. A family of anionic lipids known as the phosphoinositides (PIPs) are low in abundance, yet play a critical role in recruitment of peripheral proteins to the membrane interface. PIPs are mono-, bis-, or trisphosphorylated derivatives of phosphatidylinositol (PI) yielding seven species with different structure and anionic charge. The differential spatial distribution and temporal appearance of PIPs is key to their role in communicating information to target proteins. Selective recognition of PIPs came into play with the discovery that the substrate of protein kinase C termed pleckstrin possessed the first PIP binding region termed the pleckstrin homology (PH) domain. Since the discovery of the PH domain, more than ten PIP binding domains have been identified including PH, ENTH, FYVE, PX, and C2 domains. Representative examples of each of these domains have been thoroughly characterized to understand how they coordinate PIP headgroups in membranes, translocate to specific membrane docking sites in the cell, and function to regulate the activity of their full-length proteins. In addition, a number of novel mechanisms of PIP-mediated membrane association have emerged, such as coincidence detection – specificity for two distinct lipid headgroups. Other PIP-binding domains may also harbor selectivity for a membrane physical property such as charge or membrane curvature. This review summarizes the current understanding of the cellular distribution of PIPs and their molecular interaction with peripheral proteins.

Phospholipid composition and a polybasic motif determine D6 PROTEIN KINASE polar association with the plasma membrane and tropic responses

“…1 legend. phospholipids, or yield lipid modifications required for D6PK affinity and specificity to membranes. Such a coincident detection has been often described for the recruitment of peripheral membrane proteins (Carlton and Cullen, 2005;Hammond and Balla, 2015;Stahelin et al, 2014). Importantly, we can exclude that kinase activity might control D6PK localization, as we have previously shown that inactive YFP:D6PK maintains similar polarity and recycling kinetics to the wild-type protein .…”

Structure of the Tuberous Sclerosis Complex 2 (TSC2) N Terminus Provides Insight into Complex Assembly and Tuberous Sclerosis Pathogenesis

“…A possible targeting mechanism is the interaction with specific membrane lipids. In the case of lysosomes, phosphoinositol 3,5-bisphosphate (PI(3,5)P 2 ) is considered a marker lipid, and PH (pleckstrin homology) domains have been reported as PI(3,5)P 2 -binding module (40,41). TSC2-N does not show structural homology to PH domains but might represent a novel PI(3,5)P 2 interaction domain.…”

MOBP levels are regulated by Fyn kinase and affect the morphological differentiation of oligodendrocytes

“…MOBP proteins contain a FYVE (for 'Fab 1, YOTB, Vac 1 and EEA1') domain which is generally postulated to bind specifically to phosphatidylinositol 3-phosphate [PI(3)P] (Stahelin et al, 2014). Interestingly, it has recently been shown for the neuronal protein protrudin, that its FYVE domain binds to other phospholipids including PI(4,5)P2 (Gil et al, 2012).…”