Biology:Protein kinase C zeta type

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Protein kinase C, zeta (PKCζ), also known as PRKCZ, is a protein in humans that is encoded by the PRKCZ gene. The PRKCZ gene encodes at least two alternative transcripts, the full-length PKCζ and an N-terminal truncated form PKMζ. PKMζ is thought to be responsible for maintaining long-term memories in the brain. The importance of PKCζ in the creation and maintenance of long-term potentiation was first described by Todd Sacktor and his colleagues at the SUNY Downstate Medical Center in 1993.[1]

Structure

PKC-zeta has an N-terminal regulatory domain, followed by a hinge region and a C-terminal catalytic domain. Second messengers stimulate PKCs by binding to the regulatory domain, translocating the enzyme from cytosol to membrane, and producing a conformational change that removes auto-inhibition of the PKC catalytic protein kinase activity. PKM-zeta, a brain-specific isoform of PKC-zeta generated from an alternative transcript, lacks the regulatory region of full-length PKC-zeta and is therefore constitutively active.[2]

PKMζ is the independent catalytic domain of PKCζ and, lacking an autoinhibitory regulatory domain of the full-length PKCζ, is constitutively and persistently active, without the need of a second messenger. It was originally thought of as being a cleavage product of full-length PKCζ, an atypical isoform of protein kinase C (PKC). Like other PKC isoforms, PKCζ is a serine/threonine kinase that adds phosphate groups to target proteins. It is atypical in that unlike other PKC isoforms, PKCζ does not require calcium or diacylglycerol (DAG) to become active, but rather relies on a different second messenger, presumably generated through a phosphoinositide 3-kinase (PI3-kinase) pathway. It is now known that PKMζ is not the result of cleavage of full-length PKCζ, but rather, in the mammalian brain, is translated from its own brain-specific mRNA, that is transcribed by an internal promoter within the PKCζ gene.[2] The promoter for full-length PKCζ is largely inactive in the forebrain and so PKMζ is the dominant form of ζ in the forebrain and the only PKM that is translated from its own mRNA.

Function

PKCζ

Atypical PKC (aPKC) isoforms [zeta (this enzyme) and lambda/iota] play important roles in insulin-stimulated glucose transport. Human adipocytes contain PKC-zeta, rather than PKC-lambda/iota, as their major aPKC. Inhibition of the PKCζ enzyme inhibits insulin-stimulated glucose transport while activation of PKCζ increases glucose transport.[3]

PKMζ

PKMζ is thought to be responsible for maintaining the late phase of long-term potentiation (LTP).[4][5][6] LTP is one of the major cellular mechanisms that are widely considered to underlie learning and memory.[7] This theory arose from the observation that PKMζ perfused into neurons causes synaptic potentiation, and selective inhibitors of PKMζ like zeta inhibitory peptide (ZIP), when bath applied one hour after tetanization, inhibit the late phase or maintenance of LTP. Thus, PKMζ was thought to be both necessary and sufficient for maintaining LTP. Subsequent work showed that inhibiting PKMζ reversed LTP maintenance when applied up to 5 hours after LTP was induced in hippocampal slices, and after 22 hours in vivo. Inhibiting PKMζ in behaving animals erased spatial long-term memories in the hippocampus that were up to one month old, without affecting spatial short-term memories,[6] and erased long-term memories for fear conditioning and inhibitory avoidance in the basolateral amygdala.[8] When ZIP was injected into rats' sensorimotor cortices, it erased muscle memories for a task, even after several weeks of training.[9] In the neocortex, thought to be the site of storage for most long-term memories, PKMζ inhibition erased associative memories for conditioned taste aversion in the insular cortex, up to 3 months after training.[10][11] The protein also seems to be involved, through the nucleus accumbens, in the consolidation and reconsolidation of the memory related to drug addiction.[12] Although results from PKCζ/PKMζ-null mice demonstrate LTP and memory appear largely the same as wild-type mice,[13][14] the normal function of PKMζ in LTP and long-term memory storage was shown to be compensated by the other atypical PKC isoform, PKCι/λ in the knock-out.[15][16][17]

Alteration in PKMζ may be involved in neurodegeneration Alzheimer's disease.[18]

Inhibitors

  • 1,3,5-Trisubstituted Pyrazolines[19]

Interactions

PRKCZ has been shown to interact with:

References

  1. ↑ "Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation". Proceedings of the National Academy of Sciences of the United States of America 90 (18): 8342–8346. 1993. doi:10.1073/pnas.90.18.8342. PMID 8378304. Bibcode: 1993PNAS...90.8342S. 
  2. ↑ 2.0 2.1 "Protein kinase M zeta synthesis from a brain mRNA encoding an independent protein kinase C zeta catalytic domain. Implications for the molecular mechanism of memory". J. Biol. Chem. 278 (41): 40305–16. October 2003. doi:10.1074/jbc.M307065200. PMID 12857744. 
  3. ↑ "PKC-zeta mediates insulin effects on glucose transport in cultured preadipocyte-derived human adipocytes". J. Clin. Endocrinol. Metab. 87 (2): 716–23. February 2002. doi:10.1210/jcem.87.2.8252. PMID 11836310. 
  4. ↑ "Protein kinase Mzeta is necessary and sufficient for LTP maintenance". Nat. Neurosci. 5 (4): 295–6. 2002. doi:10.1038/nn829. PMID 11914719. 
  5. ↑ "Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation". J Neurosci 25 (8): 1979–84. 2005. doi:10.1523/JNEUROSCI.5132-04.2005. PMID 15728837. 
  6. ↑ 6.0 6.1 "Storage of spatial information by the maintenance mechanism of LTP". Science 313 (5790): 1141–4. 2006. doi:10.1126/science.1128657. PMID 16931766. Bibcode: 2006Sci...313.1141P. 
  7. ↑ "Plasticity in the human central nervous system". Brain 129 (Pt 7): 1659–73. 2006. doi:10.1093/brain/awl082. PMID 16672292. 
  8. ↑ Lu, Bai, ed (2008). "PKMζ maintains spatial, instrumental, and classically conditioned long-term memories". PLOS Biology 6 (12): 2698–706. doi:10.1371/journal.pbio.0060318. PMID 19108606. 
  9. ↑ Brezina, Vladimir, ed (2010). "Erasing Sensorimotor Memories via PKMζ Inhibition". PLOS ONE 5 (6): e11125. doi:10.1371/journal.pone.0011125. PMID 20559553. Bibcode: 2010PLoSO...511125V. 
  10. ↑ "Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKMζ". Science 317 (5840): 951–3. 2007. doi:10.1126/science.1144334. PMID 17702943. Bibcode: 2007Sci...317..951S. 
  11. ↑ "Boundary conditions for the maintenance of memory by PKMζ in neocortex". Learn. Mem. 16 (2): 122–8. 2009. doi:10.1101/lm.1183309. PMID 19181618. 
  12. ↑ "Activation of PKCzeta and PKMzeta in the nucleus accumbens core is necessary for the retrieval, consolidation and reconsolidation of the drug memory". PLOS ONE 7 (2): e30502. February 2012. doi:10.1371/journal.pone.0030502. PMID 22348011. Bibcode: 2012PLoSO...730502C. 
  13. ↑ "PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory". Nature 493 (7432): 420–3. January 2013. doi:10.1038/nature11802. PMID 23283174. Bibcode: 2013Natur.493..420V. 
  14. ↑ "Prkcz null mice show normal learning and memory". Nature 493 (7432): 416–9. January 2013. doi:10.1038/nature11803. PMID 23283171. Bibcode: 2013Natur.493..416L. 
  15. ↑ "Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice". eLife 5: e14846. 2016. doi:10.7554/eLife.14846. PMID 27187150. 
  16. ↑ "Forget me not". eLife 5: e16597. 17 May 2016. doi:10.7554/eLife.16597. PMID 27187147. 
  17. ↑ "Neuroscience: In search of the memory molecule". Nature 535 (7610): 41–2. July 2016. doi:10.1038/nature18903. PMID 27362229. Bibcode: 2016Natur.535...41F. 
  18. ↑ "Atypical protein kinase C in neurodegenerative disease I: PKMzeta aggregates with limbic neurofibrillary tangles and AMPA receptors in Alzheimer disease". J. Neuropathol. Exp. Neurol. 65 (4): 319–26. April 2006. doi:10.1097/01.jnen.0000218442.07664.04. PMID 16691113. 
  19. ↑ "Discovery and optimization of 1,3,5-trisubstituted pyrazolines as potent and highly selective allosteric inhibitors of protein kinase C-ζ". Journal of Medicinal Chemistry 57 (15): 6513–30. August 2014. doi:10.1021/jm500521n. PMID 25058929. https://figshare.com/articles/journal_contribution/2264590. 
  20. ↑ "Characterization of PDK2 activity against protein kinase B gamma". Biochemistry 41 (32): 10351–9. 2002. doi:10.1021/bi026065r. PMID 12162751. 
  21. ↑ 21.0 21.1 21.2 21.3 "14-3-3 isotypes facilitate coupling of protein kinase C-zeta to Raf-1: negative regulation by 14-3-3 phosphorylation". Biochem. J. 345 (2): 297–306. 2000. doi:10.1042/0264-6021:3450297. PMID 10620507. 
  22. ↑ "Protein kinase C [micro] is regulated by the multifunctional chaperon protein p32". J. Biol. Chem. 275 (32): 24601–7. 2000. doi:10.1074/jbc.M002964200. PMID 10831594. 
  23. ↑ 23.0 23.1 "Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C". Biochem. Biophys. Res. Commun. 307 (3): 459–65. 2003. doi:10.1016/S0006-291X(03)01187-2. PMID 12893243. 
  24. ↑ "Mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth is a protein kinase C zeta-interacting protein". J. Cell Biol. 144 (3): 403–11. 1999. doi:10.1083/jcb.144.3.403. PMID 9971736. 
  25. ↑ "Identification of a tissue-non-specific homologue of axonal fasciculation and elongation protein zeta-1". Biochem. Biophys. Res. Commun. 313 (3): 738–44. 2004. doi:10.1016/j.bbrc.2003.12.006. PMID 14697253. 
  26. ↑ "MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling". Mol. Cell. Biol. 21 (4): 1218–27. 2001. doi:10.1128/MCB.21.4.1218-1227.2001. PMID 11158308. 
  27. ↑ "Protein kinase Czeta phosphorylates nuclear factor of activated T cells and regulates its transactivating activity". J. Biol. Chem. 277 (30): 27073–80. 2002. doi:10.1074/jbc.M106983200. PMID 12021260. 
  28. ↑ "Towards a proteome-scale map of the human protein–protein interaction network". Nature 437 (7062): 1173–8. 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R. 
  29. ↑ "Nucleotide exchange factor ECT2 interacts with the polarity protein complex Par6/Par3/protein kinase Czeta (PKCzeta) and regulates PKCzeta activity". Mol. Cell. Biol. 24 (15): 6665–75. 2004. doi:10.1128/MCB.24.15.6665-6675.2004. PMID 15254234. 
  30. ↑ 30.0 30.1 "Human homologues of the Caenorhabditis elegans cell polarity protein PAR6 as an adaptor that links the small GTPases Rac and Cdc42 to atypical protein kinase C". Genes Cells 6 (2): 107–19. 2001. doi:10.1046/j.1365-2443.2001.00404.x. PMID 11260256. 
  31. ↑ "The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C". Cell 86 (5): 777–86. 1996. doi:10.1016/S0092-8674(00)80152-X. PMID 8797824. 
  32. ↑ "A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase Czeta (PKCzeta ) and PKC-related kinase 2 by PDK1". J. Biol. Chem. 275 (27): 20806–13. 2000. doi:10.1074/jbc.M000421200. PMID 10764742. 
  33. ↑ "Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment". Biochemistry 41 (2): 561–9. 2002. doi:10.1021/bi010719z. PMID 11781095. 
  34. ↑ "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science 281 (5385): 2042–5. 1998. doi:10.1126/science.281.5385.2042. PMID 9748166. Bibcode: 1998Sci...281.2042A. 
  35. ↑ "Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway". EMBO J. 18 (11): 3024–33. 1999. doi:10.1093/emboj/18.11.3024. PMID 10357815. 
  36. ↑ "Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway". Mol. Cell 8 (4): 771–80. 2001. doi:10.1016/S1097-2765(01)00361-6. PMID 11684013. 
  37. ↑ "Identification of Src as a novel atypical protein kinase C-interacting protein". Mol. Cell Biol. Res. Commun. 2 (1): 28–31. 1999. doi:10.1006/mcbr.1999.0140. PMID 10527887. 
  38. ↑ "KIBRA is a novel substrate for protein kinase Czeta". Biochem. Biophys. Res. Commun. 317 (3): 703–7. 2004. doi:10.1016/j.bbrc.2004.03.107. PMID 15081397. 

Further reading



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