Signalling through ubiquitin ligase
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Role of Ubiquitin in signalling pathways basically Proteolytic pathway involved in degradation of non functional proteins produced during stress conditions.
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Signalling through ubiquitin ligase
- 1. Signalling through Ubiquitin Ligase Made by- Akum Paul Singh Roll No.2084
- 2. What happens during Stress? An external factor that exerts a disadvantageous influence on plant Protein damage is a key event in the stress condition protein damage can be highly toxic causes the loss of function of that specific molecule the improper exposure of hydrophobic amino acid side chains, lead to the aggregation of other proteins.
- 3. How plants face protein degradation problem? inducing the transcription of a set of genes whose products, known as stress proteins, enhance survival under stress conditions Levels of damaged proteins can be reduced in two ways On the one hand, specific molecular chaperones can prevent the aggregation of damaged proteins, and catalyze their refolding On the other hand, specific proteases can degrade damaged proteins
- 4. Avram Hershko Aaron Ciechanover Irwin Rose Nobel prize in chemistry, 2004
- 5. Ubiquitin Consists of 76 amino acids, 8.5 kDa Found in all eukaryotic cells (ubiquitously) Highly Conserved Used in post- translational modification
- 6. Small protein with big function small, heat-stable, compact globular protein (76 AA) Found only in eukaryotic organisms Highly conserved
- 7. Ubiquitin Genes UBA52 RPS27A UBB UBC
- 9. Three types of Ubiquitination
- 10. Monoubiquitination Adds one ubiquitin molecule to one substrate protein residue Required before a poly chain can begin to form Membrane Trafficking, Transcription, Endocytosis
- 12. Polyubiquitination Requires one Ub linked to substrate before chain begins to form. Chains made by linking Glysine residue of Ub to a Lysine of a Ub bound to a substrate. Linking to different position on Ub leads to different results.
- 13. Lysine 48-linked polyubiquitination Linked by 48th amino acid (Lysine) Marks proteins for destruction Requires at least 4 Ub to be recognized by proteasome
- 15. E3 ligases The most varied of the three enzymes. Each E3 can attach to many different substrate proteins. Different E2, E3 pairings will recognize different proteins by distinct degradation signals.
- 16. 26S Proteasome Abundant in nucleus and cytoplasm destroys proteins marked by Ubiquitin through Lysine 48-linked polyubiquitination
- 17. 26S Proteasome Consists of central hollow cylinder (20S) 4 stacked “rings” of 7 proteins each Capped by regulatory particles (19S) that recognize ubiquitin through ubiquitin binding domains (UBDs)
- 18. Ubiquitin in Protein Degradation
- 19. Deubiquitinating enzyme (DUB) Around 100 in the human genome Some cleave the whole chain, some only cleave a set amount of Ubs DUB USP5 selectively binds a 4-ubiquitin chain and severs it.
- 20. Regulation of Protein Degradation One means of controlling Ubiquitination is regulating the activation of E3 ligases.
Editor's Notes
- There are only 3 differences in the sequence when Ub from yeast is compared to human Ub. This strong sequence conservation suggests that the vast majority of amino acids that make up Ub are essential as apparently any mutations that have occurred over evolutionary history have been removed by natural selection. Titin , largest protein - connectin, molecular spring >30,000 AA
- 7 lysines – epsilon amino group participates in isopeptide bond C-terminal glycine binds to epsilon amino group of lysine.
- Ubiquitin Binding Domains exist to interpret signals from Ubiquitinated substrates. ~20 different UBDs exist to bind to different specific shapes of Ubiquitin chains and different monoubiquitinated locations on a protein..
- This polarised residue lowers the pKa of the cysteine, allowing it to perform a nucleophilic attack on the isopeptide bond between the ubiquitin C-terminus and the substrate lysine. Unanchored M1-linked ubiquitin chains are also the primary gene product of several genes transcribed in response to genotoxic stress. Normally, however, levels of M1-linked ubiquitin chains in cells are very low, in part because the primary gene product is cleaved to monomeric ubiquitin as it’s being transcribed at the ribosome and because of the presence of a large amount of USP5, the enzyme responsible for disassembling polyubiquitin intermediates that might otherwise accumulate in the cell.