1 / 18

14-3-3 proteins, what are they really?

14-3-3 proteins, what are they really?. A little bit about the family Where they are found Structure Cell Apoptosis Nerve cells Nerve cell degeneration The future of 14-3-3. A little bit about the family. 30kDa acidic proteins 70% of the proteins is conserved on the amino acid level

analiese
Download Presentation

14-3-3 proteins, what are they really?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 14-3-3 proteins, what are they really? A little bit about the family Where they are found Structure Cell Apoptosis Nerve cells Nerve cell degeneration The future of 14-3-3

  2. A little bit about the family • 30kDa acidic proteins • 70% of the proteins is conserved on the amino acid level • Each monomer is denoted by a Greek character: β, γ, ε, ζ, η, σ, and τ • In vivo they form homo and heterodimers • Phosphoryalted or nonphosphorylated?

  3. These proteins make up 1% of all the soluble proteins in the brain 14-3-3 ε is expressed in the spermatogonia and 14-3-3 ζ is expressed in primary and secondary spermatocytes. 14-3-3 σ is found in the epithelial cells that are part of the dermal layer of the tongue. Where 14-3-3 proteins are found

  4. 14-3-3 Structure

  5. 14-3-3 S136

  6. Apoptosis R18 14-3-3 BAD Bcl-2 Cell Death Bcl-X

  7. Nerve cells: Serotonin N-Acetyltransferase Complex • AANAT is an enzyme that controls the biological clock. Research has found that 14-3-3 ζ binds with AANAT, which enhances the affinity for AANAT to bind with other substrates. • Energy measurements were made after 14-3-3 ζ bound with AANAT and then bound with acetyl-Co-A. In terms of Gibbs free energy, it bound with a ΔG of ~0.8 kcal/mol, as opposed to the large negative values with just AANAT by itself.

  8. 14-3-3:Serotonin N-Acetyltransferase Complex

  9. Nerve Cells: Parathyroid hormone receptor • It has been researched the C-terminal tail of PTHR has been identified as RSGSSSYS this strongly correlates with the 14-3-3 binding motif of RSXpSXP. • Two binding sites on PTHR for 14-3-3 • It is hypothesized 14-3-3 proteins may act as mediators between steroids and PTHR. This also could have effects on calcium regulation; the exact function of the binding is undetermined.

  10. Neurodegenerative disease: Kainic acid (Ka) • In rats the build up of Kainic acid (Ka), a neurotoxin, induces the expression of 14-3-3 ζ mRNA. • Up regulation of 14-3-3 ζ and p53 • The association with p53 for this experiment may suggest that 14-3-3 ζ may be a mediator to this type of cell death. It is hypothesized when 14-3-3 ζ binds to p53 it may change its affinity to bind with DNA sequences.

  11. Neurodegenerative disease: Spinocerebellar Ataxia type 1 (SCA1) • A neurodegenerative disease that is caused by an unusual long polyglutamine track, 82Q, in the ataxin-1 protein. • In vivo Akt phosphorylates S776 on mutant ataxin 1 this allows for 14-3-3 binding. • By binding ataxin 1 to 14-3-3 mutant ataxin 1 becomes more toxic to nerve cells because neurdegeneration cannot occur, this causes a build up of mutant ataxin 1and causes degeneration of nerve cells. • the longer the polyglutamine track the greater the binding affinity for 14-3-3 isotypes.

  12. Neurodegenerative disease: Multiple system atrophy (MSA) • This disease causes glial cytoplasmic inclusions (GCI), which are aggregates of α-synulein, found in the nucleus and the presynaptic the cell bodies of oligodendrites and Lewy bodies • One major component of the GCIs is α-synuclein, 140 amino acids long. α-synuclein can bind to 14-3-3 by the phosphorylation S129. • It is hypothesized that in MSA 14-3-3 may mediate the interaction between α-synuclein and protein kinase C (PKC). This means that 14-3-3 would be a possible cofactor for GCI formation.

  13. J.E Galvin, “Glial Cytoplasmic Inculsions”

  14. The future of 14-3-3 • In E. tenella 14-3-3 proteins are used in a mannitol cell cycle pathway, this is believed to be a part of the sporulation process. A major enzyme in the pathway is mannitol-1-phosphate dehydrogenase (M1PD) • Sm14-3-3—1 • Sm14-3-3—1 interacts with a phosphorylated s. mansoni receptor kinase-1domian, which is homologous to the mammalian transforming growth factor β receptor-1 (TGFβ) • 26 to 45% effective in preventing in mice infected with S. mansoni

  15. For Further Reading: [1] M.B. Yaffe, How do 14-3-3 proteins work? Gatekeeper phosphorylation and the molecular anvil hypothesis. FEBS Lett.513 (2002), pp. 53–57. [2] H. Fu, R.R. Subramanian, S.C Masters, 14-3-3 Proteins: Structure, Function, and Regulation. Annu. Rev. Pharmacol. Toxicol40 (2000), pp. 614-47. [3] T. Obsil, “Structural Biology of 14-3-3 protiens” www.xray.cz/xray/csca/nh/obsil.htm (2001) [4] M.B Yaffe, A.E.H. Elia, Phosphoserine/threonine-binding domains. Curr. Opin. Cell Biol.2 (2001), pp. 131-138 [5] H. Yang, S.C. Masters, H. Wang and H. Fu. Biochim. Biophys. Acta1547 (2001), pp. 313–319. [6] H. Ibelgaufts “COPE: Apoptosis” www.copewithcytokines.de/cope.cgi?000638 (2003) [7] R.R. Subramanian, S.C. Masters, H. Zhang and H. Fu. Exp. Cell Res.271 (2001), pp. 142–151. [8] M. Adachi, Y.B. Zhang, K. Imai, Mutation of BAD with in the BH3 domain impairs its phosphorylation-mediated regulation. FEBSlett.551 (2003), pp. 147-152. [9] S.C. Masters, H. Fu, 14-3-3 Proteins Mediate an Essential Anti-apoptotic Signal. J. Biol. Chem.276 (2001), pp. 45193-45200. [10] A.J. Muslin and H. Xing, 14-3-3 proteins: regulation of subcellular localization by molecular interference. Cell. Signal.19 (2000), pp. 703–709. [11] K. Toyooka et al., Isolation and the structure of the mouse 14-3-3 η chain gene and the distribution of 14-3-3 η mRNA in the mouse brain. Mole. Brain Res.100 (2002) pp. 13-20. [12] H. Tazawa, S. Takahashi, J. Zilliacus, Interaction of the parathyroid hormone receptor with the 14-3-3 protien. Biochim. Biophys. Acta160 (2003) pp. 32-38. [13] T. Obsil, R. Ghirlando, D.C. Klein, S. Gangly, F. Dyda, Crystal Structure of the 14-3-3ζ: Serotonin N-Acetyltransferase Complex: A Role for Scaffolding in Enzyme Regulation. Cell. 105 (2001), pp. 257-267. [14] T. Komori, K. Ishizawa, N. Arai, Immunoexpression of 14-3-3 proteins in glial cytoplasmic inclusions of multiple system atrophy. Acta Neuropath. 106 (2003) pp.66-70. [15] M.P. Brug, S. Goodenough, P. Wilce, Kainic acid induces 14-3-3 ζ expression in distinct regions of rat brain. Brain Res.956 (2002) pp. 110-115. [16] X. Monatano, Correspondence: Common amino acid motifs in p53, 14-3-3 and Akt protein families. FEBS Lett.507 (2001), pp. 237-240. [17] H.K. Chen et al., Interaction of Akt-Phosphorylated Ataxin-1 with 14-3-3 Mediates Neurodegeneration in Spinocerebellar Ataxia Type-1. Cell113 (2003), pp. 457-468. [18] K.K. Dev, K. Hofele, S. Barbieri, V.L. Buchman, H. Putten, Part II: α-synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharm. 45 (2003) pp. 14-44. [19] M.M. Siles-Lucas, B. Gottstein, The 14-3-3 protein: a key molecule in parasites as in other organisms. Tren. Parasite.12 (2003) pp. 575-581. [20] D. Schectman et al., The 14-3-3 protein as a vaccine candidate against schistosomiasis. Parasite Immunol.23 (2001), pp. 213-217. [21] J.E Galvin, “Glial Cytoplasmic Inculsions” .http://www.neuro.wustl.edu/people/galvin.html. (2000) [22] H. Ibelgaufts “COPE: Raf” http://www.copewithcytokines.de/cope.cgi?008043 (2002)

More Related