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PIP2 domain

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PIP2 domains (also called PIP2 clusters) 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.

Chemical properties

Phosphatidylinositol 4,5-bisphosphate (PIP2) is an anionic signaling lipid. Its polyunsaturated acyl chains exclude it from GM1 lipid rafts. 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. 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. 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.

Other

PIP2 binding proteins

PIP2/palmitate proteins

References

  1. Levental, Ilya; Christian, David A.; Wang, Yu-Hsiu; Madara, Jonathan J.; Discher, Dennis E.; Janmey, Paul A. (1 September 2009). "Calcium-Dependent Lateral Organization in Phosphatidylinositol 4,5-Bisphosphate (PIP2)- and Cholesterol-Containing Monolayers". Biochemistry. 48 (34): 8241–8248. doi:10.1021/bi9007879. PMC 2774806. PMID 19630438.
  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 (23 October 2011). "Membrane protein sequestering by ionic protein-lipid interactions". Nature. 479 (7374): 552–5. Bibcode:2011Natur.479..552V. doi:10.1038/nature10545. PMC 3409895. PMID 22020284.
  3. Wang, J; Richards, DA (15 September 2012). "Segregation of PIP2 and PIP3 into distinct nanoscale regions within the plasma membrane". Biology Open. 1 (9): 857–62. doi:10.1242/bio.20122071. PMC 3507238. PMID 23213479.
  4. Robinson, CV; Rohacs, T; Hansen, SB (September 2019). "Tools for Understanding Nanoscale Lipid Regulation of Ion Channels". Trends in Biochemical Sciences. 44 (9): 795–806. doi:10.1016/j.tibs.2019.04.001. PMC 6729126. PMID 31060927.
  5. Milne, SB; Ivanova, PT; DeCamp, D; Hsueh, RC; Brown, HA (August 2005). "A targeted mass spectrometric analysis of phosphatidylinositol phosphate species". Journal of Lipid Research. 46 (8): 1796–802. doi:10.1194/jlr.D500010-JLR200. PMID 15897608. S2CID 45134413.
  6. Hansen, SB (May 2015). "Lipid agonism: The PIP2 paradigm of ligand-gated ion channels". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (5): 620–8. doi:10.1016/j.bbalip.2015.01.011. PMC 4540326. PMID 25633344.
  7. Robinson, CV; Rohacs, T; Hansen, SB (September 2019). "Tools for Understanding Nanoscale Lipid Regulation of Ion Channels". Trends in Biochemical Sciences. 44 (9): 795–806. doi:10.1016/j.tibs.2019.04.001. PMC 6729126. PMID 31060927.
  8. Petersen, EN; Chung, HW; Nayebosadri, A; Hansen, SB (15 December 2016). "Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D." Nature Communications. 7: 13873. Bibcode:2016NatCo...713873P. doi:10.1038/ncomms13873. PMC 5171650. PMID 27976674.
  9. Yuan, Z; Pavel, MA; Wang, H; Kwachukwu, JC; Mediouni, S; Jablonski, JA; Nettles, KW; Reddy, CB; Valente, ST; Hansen, SB (14 September 2022). "Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture". Communications Biology. 5 (1): 958. doi:10.1038/s42003-022-03841-8. PMC 9472185. PMID 36104427.
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