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Introduction to ubiquitylation|
Ubiquitin is a 76 amino acids polypeptide that has an ability to be linked to other intracellular proteins via a
covalent isopeptide bond. The bond is formed between lysine residue of target protein and C-terminal
glycine of ubiquitin molecule.
Such post-translational modification of proteins named "ubiquitylation" possesses a regulatory function.
Ubiquitylation is ATP-dependent and proceeds as a hierarchical cascade of reactions catalyzed by enzymes of different types.
E1 is an ubiquitin-activating enzyme that forms a thiol ester with with the carboxyl group of Gly76.
Then an ubiquitin carrier enzyme E2 transfers the activated ubiquitin to an ubiquitin-protein ligase E3,
that directly binds ubiquitin to the substrate lysine residue.
Sometimes additional non-enzymatic adaptor proteins facilitate this process.
Ubiquitylation may result in addition of a single ubiquitin moiety or a polymeric multi-ubiquitin chain to a target protein
lysine. Multi-ubiquitin chains have different structure and topology depending of polymerization type.
Ubiquitin molecule possesses 7 inner lysine residues (Lys 6, 11, 27, 29, 33, 48, 63) that can serve as attachment
sites of the next ubiquitin moiety, resulting in formation of several chain kinds.
Different types of ubiquitylation have different impacts on the target protein fate and function.
The role of ubiquitylation in ATP-dependent proteolysis mediated by 26S proteasome was extensively studied for last two decades. Additionally, recent discoveries highlight several proteasome-independent mechanisms involved in modulation of diverse cellular functions, such as intracellular protein trafficking, chromatin silencing, DNA repair and protein-protein interactions.
Ubiquitylation site - Acceptor lysine residue(s) for ubiquitylation
Ubiquitylation type - Kind of substrate modification with mono-ubiquitin(s) or multi-ubiquitin chain(s)
E2 - Cognate ubiquitin-conjugating enzyme E2
E3 - Ubiquitin-protein ligase E3
E4/AP - Non-enzymatic adaptor protein(s)
DUB - Deubiquitylating enzyme(s)
Multiple ubiquitylation - if several ubiquitin molecules can be incorporated, but the exact type of ubiquitylation has not been determined
Pluri-ubiquitylation - multisite mono-ubiquitylation
Lys48 (as well as Lys6, Lys11, Lys27, Lys 29, Lys33 and Lys63) - linked multi-ubiquitin chain - multi-ubiquitin chain assembled through respective Lysine residue of the adjacent ubiquitin molecule
ubiquitin chain - multi-ubiquitin chain assembled through respective Lysine residue of the adjacent ubiquitin molecule
Please see "Introduction to ubiquitylation" section for additional information.
We use the term "ubiquitylation" and other ubiquitin-related terms in accordance with terminology offered by Prof. H.P.
Jennissen (Jennissen HP: Ubiquitin and the enigma of intracellular protein degradation. Eur J Biochem 1995, 231:1-30).
Despite the fact that the term "ubiquitination" is also wide-spread now, we consider "ubiquitylation" to be more correct,
as far as target proteins are modified by ubiquityl moiety. This way of spelling also corresponds to established names
of other post-translational modifications: phosphorylation, glycosylation, acetylation and so on, including modifications
with so-called ubiquitin-like proteins - SUMO, NEDD8 and ISG15 (sumoylation, neddylation and isgylation respectively).
Terms regarding ubiquitylation type are used as follows:
Mono-ubiquitylation - modification of a lysine residue with a single ubiquitin moiety
Multi-ubiquitylation - modification of a lysine residue with a polymeric ubiquitin chain (2 or more ubiquitin molecules in a chain)
Pluri-ubiquitylation - multisite mono-ubiquitylation (modification of several lysine residue with a single ubiquitin moiety)
Lys63-linked multi-ubiquitin chain - modification of a lysine residue with a multi-ubiquitin chain assembled through Lys63 of the adjacent ubiquitin molecule
We do not use the term "poly-ubiquitylation" as far as it refers to polyprotein polymerized "head-to-tail" (ubiquitin fusion protein).
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