PIP2 domain explained

PIP2 domains[1] (also called PIP2 clusters) are a type of cholesterol-independent lipid domain formed from phosphatidylinositol and positively charged proteins in the plasma membrane.[2] [3] They tend to inhibit GM1 lipid raft function.[4]

Chemical properties

Phosphatidylinositol 4,5-bisphosphate (PIP2) is an anionic signaling lipid. Its polyunsaturated acyl chains exclude it from GM1 lipid rafts.[5] [6] The multiple negative charges on PIP2 are thought to cluster proteins with positive charges residing in the plasma membrane leading to nanoscale clusters. PIP3 is also clustered away from PIP2 and away from GM1 lipid rafts.

Biological function

PIP2 domains inhibit GM1 domain function by attracting palmitoylated proteins away from GM1 lipid rafts.[7] For this to occur a protein must be both palmitoylated and bind PIP2. Presumably PIP2 could also antagonize PIP3 localization but this has not been shown directly.

PLD2

Phospholipase D2 (PLD2) binds PIP2 and localizes with lipid rafts. Increases in cholesterol overcome PIP2 binding and sequester PLD2 into GM1 lipid rafts away from its substrate phosphatidylcholine. Efflux of cholesterol causes PLD2 to translocate to PIP2 domains where it is activated by substrate presentation.[8] Both PIP2 signaling and cholesterol signaling regulate the enzyme.

ACE2 receptor

Angiotensin converting enzyme (ACE2) is regulated by PIP2 localization. The ACE2 enzyme is palmitoylated which drives the protein into GM1 lipids. The enzyme also bind to PIP2 which moves it out of the endocytic pathway. The drug hydroxychloroquine blocks ACE2 interaction with PIP2 in multiple cell types shifting its localization.[9]

Other

PIP2 binding proteins

PIP2/palmitate proteins

Notes and References

  1. Levental . Ilya . Christian . David A. . Wang . Yu-Hsiu . Madara . Jonathan J. . Discher . Dennis E. . Janmey . Paul A. . Calcium-Dependent Lateral Organization in Phosphatidylinositol 4,5-Bisphosphate (PIP2)- and Cholesterol-Containing Monolayers . Biochemistry . 1 September 2009 . 48 . 34 . 8241–8248 . 10.1021/bi9007879. 19630438 . 2774806 .
  2. van den Bogaart . G . Meyenberg . K . Risselada . HJ . Amin . H . Willig . KI . Hubrich . BE . Dier . M . Hell . SW . Grubmüller . H . Diederichsen . U . Jahn . R . Membrane protein sequestering by ionic protein-lipid interactions. . Nature . 23 October 2011 . 479 . 7374 . 552–5 . 10.1038/nature10545 . 22020284. 3409895 . 2011Natur.479..552V .
  3. Wang . J . Richards . DA . Segregation of PIP2 and PIP3 into distinct nanoscale regions within the plasma membrane. . Biology Open . 15 September 2012 . 1 . 9 . 857–62 . 10.1242/bio.20122071 . 23213479. 3507238 .
  4. Robinson . CV . Rohacs . T . Hansen . SB . Tools for Understanding Nanoscale Lipid Regulation of Ion Channels. . Trends in Biochemical Sciences . September 2019 . 44 . 9 . 795–806 . 10.1016/j.tibs.2019.04.001 . 31060927. 6729126 .
  5. Milne . SB . Ivanova . PT . DeCamp . D . Hsueh . RC . Brown . HA . 45134413 . A targeted mass spectrometric analysis of phosphatidylinositol phosphate species. . Journal of Lipid Research . August 2005 . 46 . 8 . 1796–802 . 10.1194/jlr.D500010-JLR200 . 15897608. free .
  6. Hansen . SB . Lipid agonism: The PIP2 paradigm of ligand-gated ion channels. . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . May 2015 . 1851 . 5 . 620–8 . 10.1016/j.bbalip.2015.01.011 . 25633344. 4540326 .
  7. Robinson . CV . Rohacs . T . Hansen . SB . Tools for Understanding Nanoscale Lipid Regulation of Ion Channels. . Trends in Biochemical Sciences . September 2019 . 44 . 9 . 795–806 . 10.1016/j.tibs.2019.04.001 . 31060927. 6729126 .
  8. Petersen . EN . Chung . HW . Nayebosadri . A . Hansen . SB . Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D. . Nature Communications . 15 December 2016 . 7 . 13873 . 10.1038/ncomms13873 . 27976674. 5171650 . 2016NatCo...713873P .
  9. Yuan . Z . Pavel . MA . Wang . H . Kwachukwu . JC . Mediouni . S . Jablonski . JA . Nettles . KW . Reddy . CB . Valente . ST . Hansen . SB . Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture. . Communications Biology . 14 September 2022 . 5 . 1 . 958 . 10.1038/s42003-022-03841-8 . 36104427. 9472185 .

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