PowerPointPrsentation

1
Institut für Biochemie und Molekulare Medizin
Lecture 3 Regulation of Initiation
Met-tRNA-binding Michael Altmann WS 2007/2008
2
Regulation of Met-tRNAi-binding
eIF2B
structure
function
regulation
eIF2 kinases
GCN2
PKR
HRI
PERK
Unfolded protein response
ER stress
Eukaryotic translation H. Trachsel
3
eIF2B
Factor
Reactions
Reference
Eukaryotic translation H. Trachsel
CG Proud
Sem. CellDev. Biol. 16 3-12, 2004
4
GDP exchange reaction
Eukaryotic translation H. Trachsel
5
Regulation of eIF2B activity
(Generation of stable inactive eIF2-eIF2B complex)
(Phosphorylation of ?-subunit at ser 51)
(Muations leading to degeneration of central
nervous system)
Reference
Eukaryotic translation H. Trachsel
GD Pavitt
Biochem. Soc. Trans. 33 1487-1492, 2005
6
eIF2 kinases
Reference
Eukaryotic translation H. Trachsel
CG Proud
Sem. CellDev. Biol. 16 3-12, 2005.
7
Sequesteration of eIF2B
eIF2?
eIF2?-P
kinase
eIF2
eIF2?-P
eIF2?-P-GDP
GDP
eIF2B
eIF2?-P-GDP
eIF2?-P-GDP-eIF2B
(stable!)
Eukaryotic translation H. Trachsel
8
GCN2 kinase
GCN4 mRNA translation
Regulation of LysRS expression
Eukaryotic translation H. Trachsel
9
PKR
Eukaryotic translation H. Trachsel
10
PKR and apoptosis
Reference
D. Scheuner et al.
Eukaryotic translation H. Trachsel
J.Biol.Chem. 281 21458-21468, 2006.
11
PKR activation
Reference
Eukaryotic translation H. Trachsel
M Dey et al.
Cell 122 901-913, 2005.
12
Phosphorylation of eIF2
Eukaryotic translation H. Trachsel
13
Activation of HRI
Reference
Eukaryotic translation H. Trachsel
M Rafie-Kolpin et al.
Biochem. 42 6536-6544, 2003.
14
Activation of PERK
Reference
Eukaryotic translation H. Trachsel
SJ Marciniak et al.
J. Cell Biol 172 201-209, 2006
15
The unfolded protein response
Stress situation
Normal situation
transcription
nucleus
Golgi
(stress genes)
(cleavage)
Ire1
ATF6
Ire1
ATF6
chaperones
secreted protein
BiP
eIF2alpha-
PERK
phosphoryl.
PERK
inhibition of translation
stimulation ATF4
ATF6 precursor of transcription factor
BiP is engaged in protein folding ATF6, Ire1and
PERK dimerize
Ire1 protein kinase and endonuclease (splicing
factor)
ATF6 and BiP stimulate transcription of stress
genes
PERK eIF2 kinase
PERK inhibits translation
BiP chaperone, folds secreted proteins, keeps
ATF6 in ER, inhibits dimerization of Ire1 and PERK
Eukaryotic translation H. Trachsel
Feed back inhibition of the kinase
16
Translation factors and human diseases
Reference
CM Abbott CG Proud
Eukaryotic translation H. Trachsel
Trends Biochem. Sci. 29 25-31, 2004
17
Seminar 1
- Explain to a layman how genes regulate biol.
processes!
- What are the biol. consequences of mRNA
transport and localized translation?
- Inform yourself about CCA adding enzyme (tRNA)!
- How many rRNA genes does a cell need to make
106 ribosomes in 6 hours?
- What are the most prominent differences in the
mechanism of initiation between
prokaryotes and eukaryotes?
- Why should a cell need so many helicases?
- Whats about translation in mitochondria?
- Are there orthologs of eIFs?
- How are protein-protein interactions measured?
- Why are 10-20 of eIF2?-P sufficient to block
translation?
- Physiological consequences of translational
regulation of transcription factors?
- Viruses fight against eIF2 kinases! How?
Eukaryotic translation H. Trachsel