the ubiquitin-proteasome system and its role in the cell cycle
Post on 19-Dec-2015
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The ubiquitin-proteasome system and its role in the cell
cycle
The cell cycle
How is the cell cycle regulated?
All events need to happen in the right order.Each event needs to happen once and only once!
• protein synthesis
• post-translational modifications
• protein degradation
How are proteins degraded?
• by the ubiquitin-proteasome system
Nobel prize in chemistry, 2004
Avram Hershko Aaron Ciechanover Irwin Rose
What is ubiquitin?
• 76 amino acids polypeptide• very highly conserved from plants to eukaryotes• ubiquitous (= widely distributed) to all cells• active in different cellular processes like DNA repair, cellular trafficking, endocytosis.
Its main role is in tagging proteins for degradation by poly-ubiquitin chains.
Tagging proteins with ubiquitin
Synthesis of a polyubiquitin chain on the substrate by conjugation of additional ubiquitin molecules through lysine 48.
E4
E1 - ubiquitin activating enzyme Non specific
E2 - ubiquitin conjugating enzyme
E3 - ubiquitin protein ligase Substrate specificTransfers the ubiquitin to a lysine residue of the substrate.
The poly-ubiquitin chain
1 - poly-ubiquitinated protein2- poly-ubiquitinated protein incubated with de-ubiquitinating enzyme
U5U4U3
U1
U2
1 2
The proteasome
• A 20S barrel-like core with proteolytic activity
• Two 19S regulatory subunits responsible for ubiquitin chain recognition, removal of ubiquitin and protein unfolding.
The whole proteasome (core+regulatory units) is often referred to as the 26S proteasome.
Degradation in the protasome
The poly-ubiquitinated protein is recognised by the 26S proteasome, unfolded and degraded. The ubiquitin molecules are recycled.
APC/C - the mitotic E3
• APC/C =Anaphase Promoting Complex/ Cyclosome
• 1500 KDa Multi-subunit complex (~12 subunits).
• Known to be active from metaphase through G1.
• Regulates chromatide separation and exit from mitosis.
Oscillation patterns of two APC/C substrates
Housekeeping gene
substrate 1
substrate 2
MG1
G1/S S G2
Cells were synchronised in mitosis (M) with nocodazole. They were released into fresh medium and samples were taken every two hours.
Some roles of ubiquitin-mediated protein degradation
• control of cell division• signal transduction• regulation of gene expression• immune response• embryonic development• apoptosis