Ubiquitine

The Ubiquitine is a Protéine being useful, itself, of protein marker to be eliminated.

The Ubiquitination indicates the fixing specific and controlled ubiquitine on a Protéine target. This has as a consequence the recognition then the destruction of protein marked by the proteolytic complex of the Protéasome.

Structure

The ubiquitine comprises 76 amino-acid and has a molecular Mass of approximately 8500 Da. Its structure is very preserved among the various species of Eucaryote S: the human ubiquitine and that of a yeast divide 96% of identity for their proteinic sequence.

Mechanism of action

There exist three systems of Protéolyse (destruction of proteins):

a destruction by enzymes (Protease S) digestive nonspecific: Trypsin, Pepsin, Chymotrypsine of the food protids;
the system lysosomial, nonspecific, allowing the degradation and the recycling of cellular proteins by intracellular proteases;
the system ubiquitine-protéasome, always intracellular, but this highly specific time by a system of marking of proteins to be degraded.

The ubiquitine is small a Protéine present in all the cells of the Eucaryote S. Its function principal is to mark other proteins for their destruction, which one calls the Protéolyse. Several molecules of ubiquitine are related in a covalent way to target protein (polyubiquitination), thanks to the action of three enzymes, E1, E2 and E3-ligases. The protein thus modified is then directed towards a Protéasome, a structure in form of barrel whose activity is controlled by the ubiquitine, and in which the proteolysis proceeds. The ubiquitine is then released from its substrate and can be re-used.

Sequential action of the enzymes allowing fixing other proteins: E1 fixes the ubiquitine; E1-Ubiquitine sets on E2 then transfer the ubiquitine on E2; E2-Ubiquitine is fixed on E3. The E3-E2-Ubiquitine complex is active.

E1 ( enzyme of activation of the ubiquitine ) would be single. There would exist nearly a hundred of the types of E2 ( enzyme of conjugation of ubiquitine ) and more than 1000 types of E3 ( ligase ubiquitine-protein ), the latter explaining the specificity of the reaction. E2 and E3 are often associated one with the other in the cytoplasm.

The ubiquitine can also mark transmembrane proteins (for example, receiving S) to remove them membrane.

History

In 2004, Aaron Ciechanover, Avram Hershko and Irwin Pink accepted the Nobel Prize of chemistry for their work on the degradation of proteins controlled by the ubiquitine.

Diseases implying the ubiquitine

the Syndrome of Liddle is a rare disease described for the first time in 1960 by Grant Liddle and characterized by a arterial Hypertension serious. One of the causes of the disease among others and a change of a gene coding one of the sub-units of the sodic channel ENaC, which prevents the fixing of the specific E3 enzyme called NEDD4 and thus the degradation of ENaC.
the Parkinson's disease could be also caused by the accumulation of certain secondary substances to a deficit in certain E3 enzymes.
Some Cancer S could be caused by an excessive inhibiting protein degradation, or by an accumulation of other protids because of modification of the E3 enzyme.
the system ubiquitine-protéasome would also have a role during certain viral infections.

Inhibition of the system ubiquitine-protéasome

The Bortezomib is one of the first molecules developed to this end. It was used in experiments in the treatment of the multiple Myélome.

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