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Biochimica Et Biophysica Acta Jun 2014There are six major species of phospholipids in eukaryotes, each of which plays unique structural and functional roles. One species, phosphatidylinositol (PI) only... (Review)
Review
There are six major species of phospholipids in eukaryotes, each of which plays unique structural and functional roles. One species, phosphatidylinositol (PI) only contributes about 2-10% of the total phospholipid pool. However, they are critical factors in the regulation of several fundamental processes such as in membrane dynamics and signal transduction pathways. Although numerous acyl species exist, PI species are enriched with one specific acyl chain composition at both sn-1 and sn-2 positions. Recent work has identified several enzymes that act on lipids to lead to the formation or interconversion of PI species that exhibit acyl chain specificity. These enzymes contribute to this lipid's enrichment with specific acyl chains. The nature of the acyl chains on signaling lipids has been shown to contribute to their specificity. Here we review some of the critical functions of PI and the multiple pathways in which PI can be produced and metabolized. We also discuss a common motif that may confer arachidonoyl specificity to several of the enzymes involved. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.
Topics: Acylation; Animals; Arachidonic Acid; Cell Membrane; Humans; Phosphatidylinositols
PubMed: 24120446
DOI: 10.1016/j.bbamem.2013.10.003 -
ELife Aug 2022The phosphatidylinositol 4-phosphate 5-kinase (PIP5K) family of lipid-modifying enzymes generate the majority of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] lipids...
The phosphatidylinositol 4-phosphate 5-kinase (PIP5K) family of lipid-modifying enzymes generate the majority of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] lipids found at the plasma membrane in eukaryotic cells. PI(4,5)P lipids serve a critical role in regulating receptor activation, ion channel gating, endocytosis, and actin nucleation. Here, we describe how PIP5K activity is regulated by cooperative binding to PI(4,5)P lipids and membrane-mediated dimerization of the kinase domain. In contrast to constitutively dimeric phosphatidylinositol 5-phosphate 4-kinase (PIP4K, type II PIPK), solution PIP5K exists in a weak monomer-dimer equilibrium. PIP5K monomers can associate with PI(4,5)P-containing membranes and dimerize in a protein density-dependent manner. Although dispensable for cooperative PI(4,5)P binding, dimerization enhances the catalytic efficiency of PIP5K through a mechanism consistent with allosteric regulation. Additionally, dimerization amplifies stochastic variation in the kinase reaction velocity and strengthens effects such as the recently described stochastic geometry sensing. Overall, the mechanism of PIP5K membrane binding creates a broad dynamic range of lipid kinase activities that are coupled to the density of PI(4,5)P and membrane-bound kinase.
Topics: Cell Membrane; Dimerization; Phosphates; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 35976097
DOI: 10.7554/eLife.73747 -
Biological & Pharmaceutical Bulletin Sep 2007Phosphoinositides are a family of phosphorylated derivatives of the membrane lipid phosphatidylinositol. These lipids are highly concentrated in distinct pools located... (Review)
Review
Phosphoinositides are a family of phosphorylated derivatives of the membrane lipid phosphatidylinositol. These lipids are highly concentrated in distinct pools located in a cell's plasma membrane, endosomes or nucleus, where they function as ligands for phosphoinositide-binding proteins. Protein domains that bind phosphoinositides include the pleckstrin homology (PH) domain, the phox homology (PX) domain and the Fab1p-YOPB-Vps27p-EEA1 (FYVE) domain. These domains are found in many proteins involved in intracellular signaling, membrane trafficking and cytoskeletal rearrangement. Recent studies have identified potential links between alterations to various signaling pathways involving phosphoinositides and the etiology of many human diseases.
Topics: Animals; Blood Proteins; Humans; Phosphatidylinositols; Phosphoproteins; Signal Transduction
PubMed: 17827706
DOI: 10.1248/bpb.30.1599 -
Nature Dec 2017Vesicular carriers transport proteins and lipids from one organelle to another, recognizing specific identifiers for the donor and acceptor membranes. Two important...
Vesicular carriers transport proteins and lipids from one organelle to another, recognizing specific identifiers for the donor and acceptor membranes. Two important identifiers are phosphoinositides and GTP-bound GTPases, which provide well-defined but mutable labels. Phosphatidylinositol and its phosphorylated derivatives are present on the cytosolic faces of most cellular membranes. Reversible phosphorylation of its headgroup produces seven distinct phosphoinositides. In endocytic traffic, phosphatidylinositol-4,5-biphosphate marks the plasma membrane, and phosphatidylinositol-3-phosphate and phosphatidylinositol-4-phosphate mark distinct endosomal compartments. It is unknown what sequence of changes in lipid content confers on the vesicles their distinct identity at each intermediate step. Here we describe 'coincidence-detecting' sensors that selectively report the phosphoinositide composition of clathrin-associated structures, and the use of these sensors to follow the dynamics of phosphoinositide conversion during endocytosis. The membrane of an assembling coated pit, in equilibrium with the surrounding plasma membrane, contains phosphatidylinositol-4,5-biphosphate and a smaller amount of phosphatidylinositol-4-phosphate. Closure of the vesicle interrupts free exchange with the plasma membrane. A substantial burst of phosphatidylinositol-4-phosphate immediately after budding coincides with a burst of phosphatidylinositol-3-phosphate, distinct from any later encounter with the phosphatidylinositol-3-phosphate pool in early endosomes; phosphatidylinositol-3,4-biphosphate and the GTPase Rab5 then appear and remain as the uncoating vesicles mature into Rab5-positive endocytic intermediates. Our observations show that a cascade of molecular conversions, made possible by the separation of a vesicle from its parent membrane, can label membrane-traffic intermediates and determine their destinations.
Topics: Animals; Auxilins; COS Cells; Cell Line; Cell Membrane; Chlorocebus aethiops; Clathrin; Clathrin-Coated Vesicles; Coated Pits, Cell-Membrane; Endocytosis; Endosomes; Humans; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; rab5 GTP-Binding Proteins
PubMed: 29236694
DOI: 10.1038/nature25146 -
Progress in Lipid Research Jul 2010Phosphoinositides are essential signaling molecules linked to a diverse array of cellular processes in eukaryotic cells. The metabolic interconversions of these... (Review)
Review
Phosphoinositides are essential signaling molecules linked to a diverse array of cellular processes in eukaryotic cells. The metabolic interconversions of these phospholipids are subject to exquisite spatial and temporal regulation executed by arrays of phosphatidylinositol (PtdIns) and phosphoinositide-metabolizing enzymes. These include PtdIns- and phosphoinositide-kinases that drive phosphoinositide synthesis, and phospholipases and phosphatases that regulate phosphoinositide degradation. In the past decade, phosphoinositide phosphatases have emerged as topics of particular interest. This interest is driven by the recent appreciation that these enzymes represent primary mechanisms for phosphoinositide degradation, and because of their ever-increasing connections with human diseases. Herein, we review the biochemical properties of six major phosphoinositide phosphatases, the functional involvements of these enzymes in regulating phosphoinositide metabolism, the pathologies that arise from functional derangements of individual phosphatases, and recent ideas concerning the involvements of phosphoinositide phosphatases in membrane traffic control.
Topics: Biological Transport; Carrier Proteins; Disease; Humans; Inositol Polyphosphate 5-Phosphatases; Membrane Proteins; Nerve Tissue Proteins; PTEN Phosphohydrolase; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Protein Tyrosine Phosphatases, Non-Receptor
PubMed: 20043944
DOI: 10.1016/j.plipres.2009.12.001 -
RNA Biology 2009Messenger RNA export from the nucleus to the cytoplasm plays an essential role in linking transcription to translation and consequently regulation of protein expression.... (Review)
Review
Messenger RNA export from the nucleus to the cytoplasm plays an essential role in linking transcription to translation and consequently regulation of protein expression. mRNA export requires a series of events: pre-mRNA processing, ribonucleoprotein targeting to the NPC (nuclear pore complexes), and translocation through nuclear pores to the cytoplasm. Interestingly, the conventional nuclear export machinery, exportins and the Ran GTPase, is not required for mRNA export. Instead, a protein complex consisting of a number of RNA binding proteins is essential for this event including the Aly/REF protein. Phosphoinositide signaling regulates a variety of cellular functions including pre-mRNA splicing and mRNA export. In fact, a phospholipase C-dependent inositol polyphosphate kinase pathway is required for efficient mRNA export. Recently, we showed that Aly is a physiological target of nuclear phosphoinositide-3-kinase (PI3K) signaling, which regulates Aly localization as well as Aly function in cell proliferation and mRNA export through nuclear Akt-mediated phosphorylation and phosphoinositide association. Hence, water-soluble inositol polyphosphates and phosphatidylinositol lipids play pivotal roles in modulating mRNA export.
Topics: Animals; Cell Nucleus; Cytoplasm; HeLa Cells; Humans; Models, Biological; Models, Genetic; Nuclear Pore; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phosphatidylinositols; RNA; RNA, Messenger; Signal Transduction; Type C Phospholipases
PubMed: 19106628
DOI: 10.4161/rna.6.1.7439 -
Viruses Oct 2020Phosphoinositides account for only a small proportion of cellular phospholipids, but have long been known to play an important role in diverse cellular processes, such... (Review)
Review
Phosphoinositides account for only a small proportion of cellular phospholipids, but have long been known to play an important role in diverse cellular processes, such as cell signaling, the establishment of organelle identity, and the regulation of cytoskeleton and membrane dynamics. As expected, given their pleiotropic regulatory functions, they have key functions in viral replication. The spatial restriction and steady-state levels of each phosphoinositide depend primarily on the concerted action of specific phosphoinositide kinases and phosphatases. This review focuses on a number of remarkable examples of viral strategies involving phosphoinositide kinases to ensure effective viral replication.
Topics: Animals; Caenorhabditis elegans Proteins; Humans; Organelles; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Virus Diseases; Virus Replication; Viruses
PubMed: 33022924
DOI: 10.3390/v12101124 -
Current Topics in Microbiology and... 2012Diverse biological processes including cell growth and survival require transient association of proteins with cellular membranes. A large number of these proteins are... (Review)
Review
Diverse biological processes including cell growth and survival require transient association of proteins with cellular membranes. A large number of these proteins are drawn to a bilayer through binding of their modular domains to phosphoinositide (PI) lipids. Seven PI isoforms are found to concentrate in distinct pools of intracellular membranes, and this lipid compartmentalization provides an efficient way for recruiting PI-binding proteins to specific cellular organelles. The atomic-resolution structures and membrane docking mechanisms of a dozen PI effectors have been elucidated in the last decade, offering insight into the molecular basis for regulation of the PI-dependent signaling pathways. In this chapter, I summarize the mechanistic aspects of deciphering the 'PI code' by the most common PI-recognizing domains and discuss similarities and differences in the membrane anchoring mechanisms.
Topics: Animals; Cell Membrane; Humans; Phosphatidylinositols; Protein Structure, Tertiary; Signal Transduction
PubMed: 23086416
DOI: 10.1007/978-94-007-5025-8_6 -
Nature Reviews. Molecular Cell Biology Feb 2014
Topics: Animals; Carrier Proteins; Cell Membrane; Endoplasmic Reticulum; Ergosterol; Golgi Apparatus; Homeostasis; Humans; Lipid Bilayers; Lipid Metabolism; Membrane Proteins; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phospholipid Transfer Proteins; Receptors, Steroid; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Vitamin E Deficiency
PubMed: 24434885
DOI: 10.1038/nrm3740 -
Nature Chemical Biology Jul 2010Phosphoinositide (PI) lipids are essential components of eukaryotic cell membranes. They are produced by mono-, bis- and trisphosphorylation of the inositol headgroup of... (Review)
Review
Phosphoinositide (PI) lipids are essential components of eukaryotic cell membranes. They are produced by mono-, bis- and trisphosphorylation of the inositol headgroup of phosphatidylinositol (PtdIns) and are concentrated in separate pools of cytosolic membranes. PIs serve as markers of the cell compartments and form unique docking sites for protein effectors. Collectively, seven known PIs, the protein effectors that bind them and enzymes that generate or modify PIs compose a remarkably complex protein-lipid signaling network. A number of cytosolic proteins contain one or several effector modules capable of recognizing individual PIs and recruiting the host proteins to distinct intracellular compartment. The recently determined atomic-resolution structures and membrane-targeting mechanisms of a dozen PI effectors have provided insights into the molecular basis for regulation of endocytic membrane trafficking and signaling. In this review, I highlight the structural aspects of the deciphering of the 'PI code' by the most common PI-recognizing effectors and discuss the mechanistic details of their membrane anchoring.
Topics: Gene Expression Regulation; Models, Molecular; Phosphatidylinositols; Protein Structure, Tertiary
PubMed: 20559318
DOI: 10.1038/nchembio.390