Biology:PI4K2A

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Phosphatidylinositol 4-kinase 2-alpha is an enzyme that in humans is encoded by the PI4K2A gene.[1][2][3]

Classification

This gene encodes a phosphatidylinositol 4-kinase which catalyzes phosphorylation of phosphatidylinositol at the D-4 position, yielding phosphatidylinositol 4-phosphate (PI4P). Besides the fact, that PI4P serves as a precursor for other important phosphoinositides, such as phosphatidylinositol 4,5-bisphosphate, PI4P is an essential molecule in the cellular signaling and trafficking especially in the Golgi apparatus and the trans Golgi network.

Phosphatidylinositol 4-kinases are evolutionary conserved among eukaryotes and include four human isoforms

  • phosphatidylinositol 4-kinase alpha (PI4KA)
  • phosphatidylinositol 4-kinase beta (PI4KB)
  • phosphatidylinositol 4-kinase 2-alpha (PI4K2A)
  • phosphatidylinositol 4-kinase 2-beta (PI4K2B)

Function

Phosphatidylinositol 4-kinase 2-alpha (PI4K2A) is the most abundant phosphatidylinositol 4-kinase in human cells and is responsible for the synthesis of approximately 50% of the total PI4P within the cell. PI4K2A is associated mainly with the membranes of the trans Golgi network and early and late endosomes;[4] its membrane association is achieved by a heavy palmitoylation within a specific cysteine-rich motif.[5] Besides the synthesis of phosphatidylinositol 4,5-bisphosphate, PI4K2A is involved in various cell processes including membrane trafficking, regulation of endosomal sorting promoting target protein recruitment to endosomes or trans Golgi network, or signal transduction. Particularly, it regulates e.g. targeting of clathrin adaptor complexes to the Golgi apparatus,[6] EGFR signaling,[7] or the Wnt signaling pathway.[8]

PI4K2A is important in lysosomal quality control. It is the first essential enzyme of the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair.[9] Upon lysosomal membrane damage, PI4K2A is strongly recruited to lysosomes, leading to robust lysosomal PI4P production. Such lysosomal PI4K2A/PI4P signaling drives rapid lysosomal repair through extensive membrane contacts between the endoplasmic reticulum (ER) and damaged lysosomes as well as multiple ER-to-lysosomal lipid transfer processes.

Pi4k2a gene trap mouse show pre-mature aging and neurodegeneration, with increased lipofuscin accumulation.[10] PI4K2A-deleted patients have complex and severe developmental problems along with neurodegeneration.[11]

Clinical significance

Dysfunction of PI4K2A may contribute to tumour growth,[12] spastic paraplegia,[13] Gaucher's disease,[14] or Alzheimer's disease.[15]

Structure

Cartoon representation of the kinase domain of the phosphatidylinositol 4-kinase 2-alpha. N-lobe is colored in gold, C-lobe in aquamarine, ATP in the active site between the lobes in the stick representation. PDB code: 4PLA.[16]

PI4K2A is composed of a proline-rich N-terminal region and a kinase domain located C-terminally. The proline-rich N-terminal region contains physiologically important binding sites for a ubiquitin ligase Itch [17] and clathrin adaptor complex 3,[18] but is likely disordered and dispensable for the kinase activity.[19] The kinase domain can be divided into N-terminal and C-terminal lobes with the ATP binding groove and putative phosphatidylinositol binding pocket in between. The C-lobe of the kinase domain contains an additional lateral hydrophobic pocket with no distinct function assigned yet.[16][20]

References

  1. ↑ "A novel family of phosphatidylinositol 4-kinases conserved from yeast to humans". The Journal of Biological Chemistry 276 (11): 7705–7708. March 2001. doi:10.1074/jbc.C000861200. PMID 11244087. 
  2. ↑ "Cloning of a human type II phosphatidylinositol 4-kinase reveals a novel lipid kinase family". The Journal of Biological Chemistry 276 (20): 16635–16640. May 2001. doi:10.1074/jbc.M100982200. PMID 11279162. 
  3. ↑ "Entrez Gene: PI4KII phosphatidylinositol 4-kinase type II". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55361. 
  4. ↑ "Characterization of type II phosphatidylinositol 4-kinase isoforms reveals association of the enzymes with endosomal vesicular compartments". The Journal of Biological Chemistry 277 (22): 20041–20050. May 2002. doi:10.1074/jbc.m111807200. PMID 11923287. 
  5. ↑ "Palmitoylation controls the catalytic activity and subcellular distribution of phosphatidylinositol 4-kinase II{alpha}". The Journal of Biological Chemistry 284 (15): 9994–10003. April 2009. doi:10.1074/jbc.M900724200. PMID 19211550. 
  6. ↑ "Phosphatidylinositol 4 phosphate regulates targeting of clathrin adaptor AP-1 complexes to the Golgi". Cell 114 (3): 299–310. August 2003. doi:10.1016/s0092-8674(03)00603-2. PMID 12914695. 
  7. ↑ "Phosphatidylinositol 4-kinase is required for endosomal trafficking and degradation of the EGF receptor". Journal of Cell Science 119 (Pt 3): 571–581. February 2006. doi:10.1242/jcs.02752. PMID 16443754. 
  8. ↑ "Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation". Science 321 (5894): 1350–1353. September 2008. doi:10.1126/science.1160741. PMID 18772438. 
  9. ↑ "A phosphoinositide signalling pathway mediates rapid lysosomal repair". Nature 609 (7928): 815–821. September 2022. doi:10.1038/s41586-022-05164-4. PMID 36071159. 
  10. ↑ "Loss of phosphatidylinositol 4-kinase 2alpha activity causes late onset degeneration of spinal cord axons". Proceedings of the National Academy of Sciences of the United States of America 106 (28): 11535–11539. July 2009. doi:10.1073/pnas.0903011106. PMID 19581584. 
  11. ↑ "PI4K2A deficiency in an intellectual disability, epilepsy, myoclonus, akathisia syndrome". Annals of Clinical and Translational Neurology 5 (12): 1617–1621. December 2018. doi:10.1002/acn3.677. PMID 30564627. 
  12. ↑ "PI4KIIalpha is a novel regulator of tumor growth by its action on angiogenesis and HIF-1alpha regulation". Oncogene 29 (17): 2550–2559. April 2010. doi:10.1038/onc.2010.14. PMID 20154717. 
  13. ↑ "Loss of phosphatidylinositol 4-kinase 2alpha activity causes late onset degeneration of spinal cord axons". Proceedings of the National Academy of Sciences of the United States of America 106 (28): 11535–11539. July 2009. doi:10.1073/pnas.0903011106. PMID 19581584. 
  14. ↑ "Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase". Molecular Biology of the Cell 23 (8): 1533–1545. April 2012. doi:10.1091/mbc.E11-06-0553. PMID 22337770. 
  15. ↑ "Pathophysiological concentrations of amyloid beta proteins directly inhibit rat brain and recombinant human type II phosphatidylinositol 4-kinase activity". Journal of Neurochemistry 91 (5): 1164–1170. December 2004. doi:10.1111/j.1471-4159.2004.02805.x. PMID 15569259. 
  16. ↑ 16.0 16.1 "The crystal structure of the phosphatidylinositol 4-kinase IIα". EMBO Reports 15 (10): 1085–1092. October 2014. doi:10.15252/embr.201438841. PMID 25168678. 
  17. ↑ "Phosphatidylinositol 4-kinase IIα function at endosomes is regulated by the ubiquitin ligase Itch". EMBO Reports 13 (12): 1087–1094. December 2012. doi:10.1038/embor.2012.164. PMID 23146885. 
  18. ↑ "Phosphatidylinositol-4-kinase type II alpha contains an AP-3-sorting motif and a kinase domain that are both required for endosome traffic". Molecular Biology of the Cell 19 (4): 1415–1426. April 2008. doi:10.1091/mbc.E07-12-1239. PMID 18256276. 
  19. ↑ "Analysis of the catalytic domain of phosphatidylinositol 4-kinase type II". The Journal of Biological Chemistry 277 (46): 44366–44375. November 2002. doi:10.1074/jbc.m203241200. PMID 12215430. 
  20. ↑ "Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα". Nature Communications 5: 3552. March 2014. doi:10.1038/ncomms4552. PMID 24675427. 

Further reading




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