CPEB

CPEB, or cytoplasmic polyadenylation element binding protein, is a highly conserved RNA-binding protein that promotes the elongation of the polyadenine tail of messenger RNA.[1] CPEB most commonly activates the target RNA for translation, but can also act as a repressor,[2] dependent on its phosphorylation state.[3] In animals, CPEB is expressed in several alternative splicing isoforms that are specific to particular tissues and functions, including the self-cleaving Mammalian CPEB3 ribozyme. CPEB was first identified in Xenopus oocytes and associated with meiosis;[1] a role has also been identified in the spermatogenesis of Caenorhabditis elegans.[4]

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CPEB is involved in closed-loop regulation of mRNAs that keeps them inactive. The closed-loop structure between the 3'UTR and 5'UTR inhibits translation.[5] This has been observed in Xenopus laevis in which eIF4E bound to the 5' cap interacts with Maskin bound to CPEB on the 3' UTR creating translationally inactive transcripts. This translational inhibition is lifted once CPEB is phosphorylated, displacing the Maskin binding site, allowing for the polymerization of the PolyA tail, which can recruit the translational machinery by means of PABP.[6] However, it is important to note that this mechanism has been under great scrutiny.[7]

Role in memory

Drosophila Orb2 binds to genes implicated in long-term memory. An isoform of CPEB found in the neurons of the sea slug Aplysia californica, as well as in Drosophila, mice, and humans, contains an N-terminal domain not found in other isoforms that shows high sequence similarity to prion proteins. Experiments with the Aplysia isoform expressed in yeast reveal that CPEB has a key property associated with prions: it can cause other proteins to assume alternate protein conformations that are heritable in successive generations of yeast cells. Furthermore, the functional RNA-binding form of the CPEB protein may be the prion-like state.[8] These observations have led to the suggestion that long-lasting bistable prionlike proteins play a role in the formation of long-term memory.[9] It has been suggested that "both memory storage and its underlying synaptic plasticity are mediated by the increase in. . .CPEB."[10]

Interactions

CPEB has been shown to interact with the following proteins:

References
  1. Hake, L.E.; Richter, J.D. (1994). "CPEB is a specificity factor that mediates cytoplasmic polyadenylation during Xenopus oocyte maturation". Cell. 79 (4): 617–627. doi:10.1016/0092-8674(94)90547-9. PMID 7954828.
  2. De Moor, C.H.; Richter, J.D. (1999). "Cytoplasmic polyadenylation mediate masking and unmasking of cyclin B1 mRNA". EMBO J. 18 (8): 2294–2303. doi:10.1093/emboj/18.8.2294. PMC 1171312. PMID 10205182.
  3. Mendez, R.; Barnard, D.; Richter, J.D. (2002). "Differential mRNA translation and meiotic progression require Cdc2-mediated CPEB destruction". EMBO J. 21 (7): 1833–1844. doi:10.1093/emboj/21.7.1833. PMC 125948. PMID 11927567.
  4. Luitjens, C; Gallegos, M; Kraemer, B; Kimble, J; Wickens, M (2000). "CPEB proteins control two key steps in spermatogenesis in C. elegans". Genes Dev. 14 (20): 2596–609. doi:10.1101/gad.831700. PMC 316992. PMID 11040214.
  5. Kang, MK; Han, SJ (March 2011). "Post-transcriptional and post-translational regulation during mouse oocyte maturation". BMB Rep. 3. 44 (3): 147–157. doi:10.5483/BMBRep.2011.44.3.147. PMID 21429291. Archived from the original on 2013-11-02. Retrieved 2013-12-07.
  6. Gilbert, Scott (2010). Developmental Biology. Sunderland, MA: Sinauer Associates, Inc. p. 60. ISBN 978-0-87893-384-6.
  7. Kozak, Marilyn (1 November 2008). "Faulty old ideas about translational regulation paved the way for current confusion about how microRNAs function". Gene. 2. 423 (2): 108–115. doi:10.1016/j.gene.2008.07.013. PMID 18692553.
  8. Si, K; Lindquist, S; Kandel, ER (2003). "A Neuronal Isoform of the Aplysia CPEB Has Prion-Like Properties". Cell. 115 (7): 879–91. doi:10.1016/s0092-8674(03)01020-1. PMID 14697205.
  9. Shorter, J; Lindquist, S (2005). "Prions as adaptive conduits of memory and inheritance". Nat Rev Genet. 6 (6): 435–50. doi:10.1038/nrg1616. PMID 15931169.
  10. Fioriti L et al (2015)"The Persistence of Hippocampal-Based Memory" Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3. Neuron. doi: 10.1016/j.neuron.2015.05.021
  11. Campbell ZT, Menichelli E, Friend K, Wu J, Kimble J, Williamson JR, Wickens M (2012). "Identification of a conserved interface between PUF and CPEB proteins". J Biol Chem. 287 (22): 18854–62. doi:10.1074/jbc.M112.352815. PMC 3365739. PMID 22496444.
  12. Lin, CL.; Evans, V.; Shen, S.; Xing, Y.; Richter, JD. (Feb 2010). "The nuclear experience of CPEB: implications for RNA processing and translational control". RNA. 16 (2): 338–48. doi:10.1261/rna.1779810. PMC 2811663. PMID 20040591.
  13. Campbell, ZT.; Menichelli, E.; Friend, K.; Wu, J.; Kimble, J.; Williamson, JR.; Wickens, M. (May 2012). "Identification of a conserved interface between PUF and CPEB proteins". J Biol Chem. 287 (22): 18854–62. doi:10.1074/jbc.M112.352815. PMC 3365739. PMID 22496444.


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