Proteopedia

Phosphatidylinositol 4-kinase


Function

Phosphatidylinositol 4-kinase (PI4K) modulates inter-organelle lipid tarfficking. phosphoinositide signalling and intracellular vescicle trafficking. The catalytic domain of PI4K is required for the synthesis of phosphatidylinositol 4-phosphate[1]. The mammalian PI4K are classified into 2 types - II and III - based on their molecular mass and modulation by detergent and adenosine.

  • Phosphatidylinositol 4-kinase IIα accounts for the bulk of PI4K activity in the brain and is concentrated at synapses[2].
  • Phosphatidylinositol 4-kinase IIβ synthesises phosphatidylinositok 4,5-bisphosphate at the plasma membrane[3].
  • Phosphatidylinositol 4-kinase IIIα catalyses the synthesis of phosphatidylinositol 4-phosphate in hepatitis C virus cells[4].
  • Phosphatidylinositol 4-kinase IIIβ is a key enzyme in the control of spingomyelin synthesis by controlling the flow of ceramide from the endoplasmic reticulum to the Golgi compartment[5].

Relevance

Phosphatidylinositol 4-kinase IIIβ is required for cellular entry by pseudoviruses bearing the SARS-CoV spike protein. Inhibitors of hPI4KIIIβ blocked the entry of SARS pseudoviruses into cells[6].

Structural highlights

The 3D structure of phosphatidylinositol 4-kinase IIIβ complex with an inhibitor shows the making various [7]. Based on superposition of this structure on others with PI4K bound to ATP it is evident that the inhibitor's 5-member ring overlap the adenine ring of ATP suggesting that this inhibitor functions by sterically blocking the binding of ATP to the enzyme.



Human phosphatidylinositol 4-kinase IIIβ complex with an inhibitor (PDB code 4wag)

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3D structures of phosphatidylinositol 4-kinase3D structures of phosphatidylinositol 4-kinase

Updated on 21-July-2024

ReferencesReferences

  1. ↑ Clayton EL, Minogue S, Waugh MG. Mammalian phosphatidylinositol 4-kinases as modulators of membrane trafficking and lipid signaling networks. Prog Lipid Res. 2013 Jul;52(3):294-304. doi: 10.1016/j.plipres.2013.04.002. Epub , 2013 Apr 19. PMID:23608234 doi:http://dx.doi.org/10.1016/j.plipres.2013.04.002
  2. ↑ Guo J, Wenk MR, Pellegrini L, Onofri F, Benfenati F, De Camilli P. Phosphatidylinositol 4-kinase type IIalpha is responsible for the phosphatidylinositol 4-kinase activity associated with synaptic vesicles. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3995-4000. doi:, 10.1073/pnas.0230488100. Epub 2003 Mar 19. PMID:12646710 doi:http://dx.doi.org/10.1073/pnas.0230488100
  3. ↑ Wei YJ, Sun HQ, Yamamoto M, Wlodarski P, Kunii K, Martinez M, Barylko B, Albanesi JP, Yin HL. Type II phosphatidylinositol 4-kinase beta is a cytosolic and peripheral membrane protein that is recruited to the plasma membrane and activated by Rac-GTP. J Biol Chem. 2002 Nov 29;277(48):46586-93. PMID:12324459 doi:10.1074/jbc.M206860200
  4. ↑ Reiss S, Harak C, Romero-Brey I, Radujkovic D, Klein R, Ruggieri A, Rebhan I, Bartenschlager R, Lohmann V. The lipid kinase phosphatidylinositol-4 kinase III alpha regulates the phosphorylation status of hepatitis C virus NS5A. PLoS Pathog. 2013 May;9(5):e1003359. PMID:23675303 doi:10.1371/journal.ppat.1003359
  5. ↑ Toth B, Balla A, Ma H, Knight ZA, Shokat KM, Balla T. Phosphatidylinositol 4-kinase IIIbeta regulates the transport of ceramide between the endoplasmic reticulum and Golgi. J Biol Chem. 2006 Nov 24;281(47):36369-77. doi: 10.1074/jbc.M604935200. Epub 2006, Sep 26. PMID:17003043 doi:http://dx.doi.org/10.1074/jbc.M604935200
  6. ↑ Yang N, Ma P, Lang J, Zhang Y, Deng J, Ju X, Zhang G, Jiang C. Phosphatidylinositol 4-kinase IIIbeta is required for severe acute respiratory syndrome coronavirus spike-mediated cell entry. J Biol Chem. 2012 Mar 9;287(11):8457-67. doi: 10.1074/jbc.M111.312561. Epub 2012 , Jan 17. PMID:22253445 doi:http://dx.doi.org/10.1074/jbc.M111.312561
  7. ↑ Mejdrova I, Chalupska D, Kogler M, Sala M, Plackova P, Baumlova A, Hrebabecky H, Prochazkova E, Dejmek M, Guillon R, Strunin D, Weber J, Lee G, Birkus G, Mertlikova-Kaiserova H, Boura E, Nencka R. Highly Selective Phosphatidylinositol 4-Kinase IIIbeta Inhibitors and Structural Insight into Their Mode of Action. J Med Chem. 2015 May 14;58(9):3767-93. doi: 10.1021/acs.jmedchem.5b00499. Epub, 2015 May 4. PMID:25897704 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00499

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