Phosphatidylinositol 4,5-bisphosphate

Last updated
Phosphatidylinositol 4,5-bisphosphate
Phosphatidylinositol-4,5-bisphosphate.svg
Names
IUPAC name
1,2-Diacyl-sn-glycero-3-phospho-(1-D-myo-inositol 4,5-bisphosphate)
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
  • InChI=1S/C47H85O19P3/c1-3-5-7-9-11-13-15-17-19-20-22-24-26-28-30-32-34-36-41(49)63-39(37-61-40(48)35-33-31-29-27-25-23-21-18-16-14-12-10-8-6-4-2)38-62-69(59,60)66-45-42(50)43(51)46(64-67(53,54)55)47(44(45)52)65-68(56,57)58/h11,13,17,19,22,24,28,30,39,42-47,50-52H,3-10,12,14-16,18,20-21,23,25-27,29,31-38H2,1-2H3,(H,59,60)(H2,53,54,55)(H2,56,57,58)/p-5/b13-11-,19-17-,24-22-,30-28-/t39?,42-,43+,44+,45-,46-,47-/m1/s1 X mark.svgN
    Key: CNWINRVXAYPOMW-WJUYXORRSA-I X mark.svgN
  • InChI=1/C47H85O19P3/c1-3-5-7-9-11-13-15-17-19-20-22-24-26-28-30-32-34-36-41(49)63-39(37-61-40(48)35-33-31-29-27-25-23-21-18-16-14-12-10-8-6-4-2)38-62-69(59,60)66-45-42(50)43(51)46(64-67(53,54)55)47(44(45)52)65-68(56,57)58/h11,13,17,19,22,24,28,30,39,42-47,50-52H,3-10,12,14-16,18,20-21,23,25-27,29,31-38H2,1-2H3,(H,59,60)(H2,53,54,55)(H2,56,57,58)/p-5/b13-11-,19-17-,24-22-,30-28-/t39?,42-,43+,44+,45-,46-,47-/m1/s1
    Key: CNWINRVXAYPOMW-XHXVUCGABS
  • O=P([O-])([O-])O[C@@H]1[C@@H](O)[C@H](OP([O-])(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC)[C@H](O)[C@H](O)[C@H]1OP([O-])([O-])=O
Properties
C47H80O19P3
Molar mass 1042.05 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. [1] PIP2 also forms lipid clusters [2] that sort proteins. [3] [4] [5]

Contents

PIP2 is formed primarily by the type I phosphatidylinositol 4-phosphate 5-kinases from PI(4)P. In metazoans, PIP2 can also be formed by type II phosphatidylinositol 5-phosphate 4-kinases from PI(5)P. [6]

The fatty acids of PIP2 are variable in different species and tissues, but the most common fatty acids are stearic in position 1 and arachidonic in 2. [7]

Signaling pathways

PIP2 is a part of many cellular signaling pathways, including PIP2 cycle, PI3K signalling, and PI5P metabolism. [8] Recently, it has been found in the nucleus [9] with unknown function.

Functions

Cytoskeleton dynamics near membranes

PIP2 regulates the organization, polymerization, and branching of filamentous actin (F-actin) via direct binding to F-actin regulatory proteins. [10]

Endocytosis and exocytosis

The first evidence that indicated phosphoinositides(PIs) (especially PI(4,5)P2) are important during the exocytosis process was in 1990. Emberhard et al. [11] found that the application of PI-specific phospholipase C into digitonin-permeabilized chromaffin cells decreased PI levels, and inhibited calcium-triggered exocytosis. This exocytosis inhibition was preferential for an ATP-dependent stage, indicating PI function was required for secretion. Later studies identified associated proteins necessary during this stage, such as phosphatidylinositol transfer protein , [12] and phosphoinositol-4-monophosphatase 5 kinase type Iγ (PIPKγ) , [13] which mediates PI(4,5)P2 restoration in permeable cell incubation in an ATP-dependent way. In these later studies, PI(4,5)P2 specific antibodies strongly inhibited exocytosis, thus providing direct evidence that PI(4,5)P2 plays a pivotal role during the LDCV (Large dense core vesicle) exocytosis process.[ citation needed ]

Through the use of PI-specific kinase/phosphatase identification and PI antibody/drug/blocker discovery, the role of PI (especially PI(4,5)P2) in secretion regulation was extensively investigated. Studies utilizing PHPLCδ1 domain over-expression (acting as PI(4,5)P2 buffer or blocker) , [14] PIPKIγ knockout in chromaffin cell [15] and in central nerve system, [16] PIPKIγ knockdown in beta cell lines , [17] and over-expression of membrane-tethered inositol 5-phosphatase domain of synaptojanin 1 , [18] all suggested vesicle (synaptic vesicle and LDCV) secretion were severely impaired after PI(4,5)P2 depletion or blockage. Moreover, some studies [18] [16] [15] showed an impaired/reduced RRP of those vesicles, though the docked vesicle number were not altered [15] after PI(4,5)P2 depletion, indicating a defect at a pre-fusion stage (priming stage). Follow-up studies indicated that PI(4,5)P2 interactions with CAPS, [19] Munc13 [20] and synaptotagmin1 [21] are likely to play a role in this PI(4,5)P2 dependent priming defect.

IP3/DAG pathway

PIP2 functions as an intermediate in the IP3/DAG pathway, which is initiated by ligands binding to G protein-coupled receptors activating the Gq alpha subunit. PtdIns(4,5)P2 is a substrate for hydrolysis by phospholipase C (PLC), a membrane-bound enzyme activated through protein receptors such as α1 adrenergic receptors. PIP2 regulates the function of many membrane proteins and ion channels, such as the M-channel. The products of the PLC catalyzation of PIP2 are inositol 1,4,5-trisphosphate (InsP3; IP3) and diacylglycerol (DAG), both of which function as second messengers. In this cascade, DAG remains on the cell membrane and activates the signal cascade by activating protein kinase C (PKC). PKC in turn activates other cytosolic proteins by phosphorylating them. The effect of PKC could be reversed by phosphatases. IP3 enters the cytoplasm and activates IP3 receptors on the smooth endoplasmic reticulum (ER), which opens calcium channels on the smooth ER, allowing mobilization of calcium ions through specific Ca2+ channels into the cytosol. Calcium participates in the cascade by activating other proteins. [22]

Docking phospholipids

Class I PI 3-kinases phosphorylate PtdIns(4,5)P2 forming phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) and PtdIns(4,5)P2 can be converted from PtdIns4P. PtdIns4P, PtdIns(3,4,5)P3 and PtdIns(4,5)P2 not only act as substrates for enzymes but also serve as docking phospholipids that bind specific domains that promote the recruitment of proteins to the plasma membrane and subsequent activation of signaling cascades. [23] [24]

Potassium channels

Inwardly rectifying potassium channels have been shown to require docking of PIP2 for channel activity. [26] [27]

G protein-coupled receptors

PtdIns(4,5)P2 has been shown to stabilize the active states of Class A G protein-coupled receptors (GPCRs) via direct binding, and enhance their selectivity toward certain G proteins. [28]

G protein-coupled receptor kinases

PIP2 has been shown to recruit G protein-coupled receptor kinase 2 (GRK2) to the membrane by binding to the large lobe of GRK2. This stabilizes GRK2 and also orients it in a way that allows for more efficient phosphorylation of the beta adrenergic receptor, a type of GPCR. [29]

Regulation

PIP2 is regulated by many different components. One emerging hypothesis is that PIP2 concentration is maintained locally. Some of the factors involved in PIP2 regulation are: [30]

Related Research Articles

<span class="mw-page-title-main">Phosphatidylinositol</span> Chemical compound

Phosphatidylinositol consists of a family of lipids made of a phosphate group, two fatty acid chains, and one inositol molecule. They represent a class of the phosphatidylglycerides. Typically phosphatidylinositols form a minor component on the cytosolic side of eukaryotic cell membranes. The phosphate group gives the molecules a negative charge at physiological pH.

<span class="mw-page-title-main">Inositol phosphate</span>

Inositol phosphates are a group of mono- to hexaphosphorylated inositols. Each form of inositol phosphate is distinguished by the number and position of the phosphate group on the inositol ring.

<span class="mw-page-title-main">Phosphoinositide phospholipase C</span>

Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. These enzymes belong to a larger superfamily of Phospholipase C. Other families of phospholipase C enzymes have been identified in bacteria and trypanosomes. Phospholipases C are phosphodiesterases.

<span class="mw-page-title-main">Phosphatidylinositol (3,4,5)-trisphosphate</span> Chemical compound

Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid that resides on the plasma membrane.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

<span class="mw-page-title-main">Phosphatidylinositol 3,4-bisphosphate</span>

Phosphatidylinositol (3,4)-bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)P2 at the plasma membrane activates a number of important cell signaling pathways.

Phosphatidylinositol 3,5-bisphosphate is one of the seven phosphoinositides found in eukaryotic cell membranes. In quiescent cells, the PtdIns(3,5)P2 levels, typically quantified by HPLC, are the lowest amongst the constitutively present phosphoinositides. They are approximately 3 to 5-fold lower as compared to PtdIns3P and PtdIns5P levels, and more than 100-fold lower than the abundant PtdIns4P and PtdIns(4,5)P2. PtdIns(3,5)P2 was first reported to occur in mouse fibroblasts and budding yeast S. cerevisiae in 1997. In S. cerevisiae PtdIns(3,5)P2 levels increase dramatically during hyperosmotic shock. The response to hyperosmotic challenge is not conserved in most tested mammalian cells except for differentiated 3T3L1 adipocytes.

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction

<span class="mw-page-title-main">ENTH domain</span> InterPro Domain

The epsin N-terminal homology (ENTH) domain is a structural domain that is found in proteins involved in endocytosis and cytoskeletal machinery.

<span class="mw-page-title-main">PX domain</span>

The PX domain is a phosphoinositide-binding structural domain involved in targeting of proteins to cell membranes.

Synaptojanin is a protein involved in vesicle uncoating in neurons. This is an important regulatory lipid phosphatase. It dephosphorylates the D-5 position phosphate from phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and Phosphatidylinositol (4,5)-bisphosphate(PIP2). It belongs to family of 5-phosphatases, which are structurally unrelated to D-3 inositol phosphatases like PTEN. Other members of the family of 5'phosphoinositide phosphatases include OCRL, SHIP1, SHIP2, INPP5J, INPP5E, INPP5B, INPP5A and SKIP.

<span class="mw-page-title-main">Phospholipase C</span> Class of enzymes

Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in eukaryotic cell physiology, in particular signal transduction pathways. Phospholipase C's role in signal transduction is its cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), which serve as second messengers. Activators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids.

<span class="mw-page-title-main">PIKFYVE</span> Protein-coding gene in the species Homo sapiens

PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene.

<span class="mw-page-title-main">PIP5K1A</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol-4-phosphate 5-kinase type-1 alpha is an enzyme that in humans is encoded by the PIP5K1A gene.

<span class="mw-page-title-main">CADPS</span> Protein-coding gene in the species Homo sapiens

Calcium-dependent secretion activator 1 is a protein that in humans is encoded by the CADPS gene.

Phosphatidylinositol 5-phosphate (PtdIns5P) is a phosphoinositide, one of the phosphorylated derivatives of phosphatidylinositol (PtdIns), that are well-established membrane-anchored regulatory molecules. Phosphoinositides participate in signaling events that control cytoskeletal dynamics, intracellular membrane trafficking, cell proliferation and many other cellular functions. Generally, phosphoinositides transduce signals by recruiting specific phosphoinositide-binding proteins to intracellular membranes.

<span class="mw-page-title-main">VAC14</span> Protein-coding gene in the species Homo sapiens

Protein VAC14 homolog, also known as ArPIKfyve, is a protein that in humans is encoded by the VAC14 gene.

Phosphatidylinositol-4-phosphate 5-kinases are a class of enzymes that phosphorylate phosphatidylinositol 4-phosphate. They perform this reaction on the fifth hydroxyl of the myo-inositol ring to form phosphatidylinositol 4,5-bisphosphate.

The PI(4,5)P2 cycle or simply PIP2 cycle (also known as PI cycle in past) is one of the important signalling cascades underlying many cellular functions including GPCR signaling, cytokinesis, endocytosis, and apoptosis.

PIP2 domains are a type of cholesterol-independent lipid domain formed from phosphatidylinositol and positively charged proteins in the plasma membrane. They tend to inhibit GM1 lipid raft function.

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