Chemistry:PIP2 domain
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
References
- ↑ 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. PMID 19630438.
- ↑ van den Bogaart, G; Meyenberg, K; Risselada, HJ; Amin, H; Willig, KI; Hubrich, BE; Dier, M; Hell, SW et al. (23 October 2011). "Membrane protein sequestering by ionic protein-lipid interactions.". Nature 479 (7374): 552–5. doi:10.1038/nature10545. PMID 22020284. Bibcode: 2011Natur.479..552V.
- ↑ 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. PMID 23213479.
- ↑ 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. PMID 31060927.
- ↑ 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.
- ↑ 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. PMID 25633344.
- ↑ 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. PMID 31060927.
- ↑ 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. doi:10.1038/ncomms13873. PMID 27976674. Bibcode: 2016NatCo...713873P.
- ↑ Yuan, Z; Pavel, MA; Wang, H; Kwachukwu, JC; Mediouni, S; Jablonski, JA; Nettles, KW; Reddy, CB et al. (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. PMID 36104427.
 |  |
