Ubiquitin Structure & Function: Difference between revisions
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Ubiquitin is a single 8565 M<sub>r</sub> polypeptide consisting of 76 amino acid residues. Ubiquitin is highly known for its role in ATP-dependant protein degradation<ref> | Ubiquitin is a single 8565 M<sub>r</sub> polypeptide consisting of 76 amino acid residues. Ubiquitin is highly known for its role in ATP-dependant protein degradation<ref name="mainpaper">PMID: 3041007</ref> | ||
{{STRUCTURE_1ubq | PDB=1ubq | SCENE= }} | {{STRUCTURE_1ubq | PDB=1ubq | SCENE= }} | ||
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[[image:lysubq.png| thumb |right | upright=2.0 |Ubiquitin structure with lysine residues highlighted in Yellow.]] | [[image:lysubq.png| thumb |right | upright=2.0 |Ubiquitin structure with lysine residues highlighted in Yellow.]] | ||
=Function= | =Function= | ||
At first, ubiquitin was believed to be a hormone involed in inducing the differentiation of lymphocytes and activating adenylate cyclase <ref | At first, ubiquitin was believed to be a hormone involed in inducing the differentiation of lymphocytes and activating adenylate cyclase <ref name="2.8Aref">PMID: 2987935</ref>. However, today, ubiquitin is primarily known for its role in intracellular ATP-dependent protein degradation. This is accomplished through the process of several seperate reactions: | ||
=== Activation === | === Activation === | ||
The first step of ubiquitin activation involves the formation of a ubiqiotin-adenylate intermediate. This reaction requires an E1 ubiquitin-activating enzyme. The second step of ubiquitin activation transfers ubiquitin to the E1 active site cysteine residue and AMP is released. This step results in a thioester linkage between the C-terminal carboxyl group of ubiquitin and the E1 cysteine sulfhydryl group. | The first step of ubiquitin activation involves the formation of a ubiqiotin-adenylate intermediate. This reaction requires an E1 ubiquitin-activating enzyme. The second step of ubiquitin activation transfers ubiquitin to the E1 active site cysteine residue and AMP is released. This step results in a thioester linkage between the C-terminal carboxyl group of ubiquitin and the E1 cysteine sulfhydryl group. | ||
=== Ubiquitin Conjugation === | === Ubiquitin Conjugation === | ||
The activated ubiquitin in then transferred to a ubiquitin-conjugating enzyme, E2 through a trans-thiolesteration reaction. Ubiquitin is then transferred to the ε-amino group of a lysine chain on the target protein. An isopeptide bond is now formed between the carboxyl terminal of ubiquitin and the ε-amino group of the target protein lysine residue. This is accomplished by E2 directly. | The activated ubiquitin in then transferred to a ubiquitin-conjugating enzyme, E2 through a trans-thiolesteration reaction. Ubiquitin is then transferred to the ε-amino group of a lysine chain on the target protein. An isopeptide bond is now formed between the carboxyl terminal of ubiquitin and the ε-amino group of the target protein lysine residue. This is accomplished by E2 directly. | ||
[[Image:diubq.png| thumb |none | upright=2.0 |Isopeptide bond between two Ubiquitin molecules]] | [[Image:diubq.png| thumb |none | upright=2.0 |Isopeptide bond between two Ubiquitin molecules]] | ||
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[[Image:Ubq_pathway.png| thumb |centre | upright=2.0 |Ubiquitinylation pathway]] | [[Image:Ubq_pathway.png| thumb |centre | upright=2.0 |Ubiquitinylation pathway]] | ||
=== Proofreading === | === Proofreading === | ||
Before degradation is complete, the system must ensure that the protein that has been ubiquitinylated is in fact damaged. Enzymes associated with proofreading with either inhibit or stimulate ubiquitin-dependent processes. If the target protein is found to not be damaged, deconjugation of ubiquitin from mono- or polyubiquitinylated proteins will result in order to inhibit any further degradation processes. This reverse reaction is known as a "futile cycle"<ref> | Before degradation is complete, the system must ensure that the protein that has been ubiquitinylated is in fact damaged. Enzymes associated with proofreading with either inhibit or stimulate ubiquitin-dependent processes. If the target protein is found to not be damaged, deconjugation of ubiquitin from mono- or polyubiquitinylated proteins will result in order to inhibit any further degradation processes. This reverse reaction is known as a "futile cycle"<ref name="Ubproteindeg">PMID: 3022650</ref>. This is done through the actions of deubiquitinating thiol proteases which recognize the native conformation of ubiquitin and cleave the isopeptide bond located at the carboxyl-terminal G76 of ubiquitin<ref name="regulation">PMID: 9409543</ref>. | ||
=== Conjugate Metabolism === | === Conjugate Metabolism === | ||
If, however, the target protein is found to be damaged, the ubiquitinylated protein is lead to its degradation by the 26S proteasome<ref>Hochstrasser, M. 1996. Ubiquitin-dependent protein Degradation. Annu Rev Genet. 30: 405-439</ref>. The 26S proteasome is made up of a 20S core and a 19S cap. The targeted protein must be unfolded, deubiquitinylated and translocated through the 19S cap channels and into the proteasome interior. The 20S proteasome than cleaves the polypeptide into short peptides of roughly 7-9 fragment residues. This process is ATP-independent. Cytosolic peptidases then degrades the fragment into its appropriate amino acids. The ubiquitin molecules are returned to the cell where they are reused. | If, however, the target protein is found to be damaged, the ubiquitinylated protein is lead to its degradation by the 26S proteasome<ref>Hochstrasser, M. 1996. Ubiquitin-dependent protein Degradation. Annu Rev Genet. 30: 405-439</ref>. The 26S proteasome is made up of a 20S core and a 19S cap. The targeted protein must be unfolded, deubiquitinylated and translocated through the 19S cap channels and into the proteasome interior. The 20S proteasome than cleaves the polypeptide into short peptides of roughly 7-9 fragment residues. This process is ATP-independent. Cytosolic peptidases then degrades the fragment into its appropriate amino acids. The ubiquitin molecules are returned to the cell where they are reused. | ||
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=Types of Ubiquitin Conjugates= | =Types of Ubiquitin Conjugates= | ||
There are 3 different types of ubiquitin conjugates known: | There are 3 different types of ubiquitin conjugates known: | ||
=== Ubiquitinylation === | |||
=Diseases= | =Diseases= | ||
<references/> | <references/> | ||
