Ubiquitin-activating enzymes, also known as E1 enzymes, catalyze the first step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process covalently attaches ubiquitin, a short protein of 76 amino acids, to a lysine residue on the target protein. Once a protein has been tagged with one ubiquitin molecule, additional rounds of ubiquitination form a polyubiquitin chain that is recognized by the proteasome's 19S regulatory particle, triggering the ATP-dependent unfolding of the target protein that allows passage into the proteasome's 20S core particle, where proteases degrade the target into short peptide fragments for recycling by the cell.
The E1 reaction is itself ATP-dependent and begins with ATP hydrolysis coupled to adenylation of a molecule of free ubiquitin. The adenylated ubiquitin is transferred to the E1's active site cysteine residue in concert with the adenylation of a second molecule of ubiquitin, which is then transferred to the active-site cysteine residue of the next enzyme in the ubiquitination catalytic chain, the ubiquitin-conjugating enzyme or E2. The reaction in which the ubiquitin is attached to the target protein is performed by the third class of molecules in the chain, the ubiquitin ligases or E3s.
In most cells there are only a few different types of E1 and E2 enzymes, but many different types of E3s. It is the E3 that binds the substrate and therefore confers substrate specificity.
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