Coincidence detection in phosphoinositide signaling

Abstract

Phosphoinositide lipids function as both signaling molecules and as compartment-specific localization signals for phosphoinositide-binding proteins. In recent years, both phosphoinositides and phosphoinositide-binding proteins have been reported to display a restricted, rather than a uniform, distribution across intracellular membranes. Here, we examine recent data documenting the restricted distribution of both phosphoinositides and phosphoinositide-binding proteins and examine how phosphoinositide-binding proteins might engage multiple binding partners to achieve these restricted localizations, effectively acting as detectors of coincident localization signals.

Figure 1

Phosphoinositide species. Phosphatidylinositol (PtdIns) consists of a D-myo-inositol 1-phosphate headgroup attached, almost exclusively, to 1-stearoyl, 2-arachanonyl, 3-phosphoglycerol as depicted. A variety of phosphoinositide kinases and phosphatases act to generate various phosphorylated derivatives, as indicated.

Figure 2

Phosphoinositide-binding domains. Structural examples of modular phosphoinositide-binding domains in complex with phosphoinositide-headgroup ligands and oriented such that the membrane interaction surface is top-most. Alpha-helices rendered in blue, beta-sheets in red. (a) Grp1 PH domain in complex with Ins(1,3,4,5)P₄ [70]. (b) p40^phox PX domain in complex with di-C₄-PtdIns(3)P [71]. (c) Homodimeric EEA1 FYVE-domain (truncated to residues 1335–1411) in complex with Ins(1,3) P2. Green spheres represent Zn²⁺ ions [72]. (d) Epsin-1 ENTH-domain in complex with Ins(1,4,5)P₃ [73]. Structures were manipulated in Deepview 3.7 and rendered using POV-ray 3.6.

Figure 3

Cartoon depicting intracellular membranes in the endocytic and biosynthetic pathways and their hypothesized phosphoinositide content. These organelles control the trafficking of cargo to a variety of subcellular localizations. Organelle names given in type, trafficking pathways given by letters. A, internalization from the plasma membrane; B, degradative sorting to the lysosome; C, recycling from endosomes to the plasma membrane; D, retrieval of cargo from endosomes back to the trans-Golgi network (TGN); E, delivery of cargo from the TGN to endosomes; F, secretion of cargo from the TGN to the plasma membrane.

Figure 4

Coincidence detection to restrict localization. It is predicted that the following mechanisms will contribute towards the restricted localization of phosphoinositide-binding proteins across membrane. (a) Detection of phosphoinositides and small monomeric GTPases. Exemplified by the Arf1 and PtdIns(4)P-dependent localization of FAPP1 to the TGN. (b) Detection of phosphoinositides and cargo. Exemplified by the cargo and PtdIns(4,5)P₂-dependent localization of the adaptor protein AP-2 complex to the plasma membrane. (c) Detection of phosphoinositides and other membrane lipids. Exemplified by the hypothetical PtdIns(3,4)P₂- and PtdOH-dependent localization of p47^phox. (d) Detection of phosphoinositides and geometric cues. Exemplified by the 3′-phosphoinositide and curvature-dependent localization of SNX1 to endosomes.

Figure 5

Intermolecular coincidence detection. Oligomerization of PLCγ1 and the TrpC3 Ca²⁺ channel creates a PtdIns(4,5)P₂-binding PH domain from two half-PH domains.