Régulation de la dégradation des protéines

Cells need to regulate their levels of intracellular proteins according to the alterations in their state, such as environmental stimuli, or other metabolic or developmental changes.  This regulation or control of protein concentrations inside a cell depends on their rate of synthesis as well as their degradation.  In eukaryotes, intracellular protein degradation is mostly mediated by the ubiquitin-proteasome system. This system serves two primary functions inside the cells – the quality control of misfolded or damaged proteins, and the control of the levels of important cellular proteins.  The specificity of the proteasomal degradation in the cell is regulated through various mechanisms.  Eukaryotic cells have a class of proteins called E3 ligases – the main catalytic unit of ubiquitin ligase. Each of these unique E3 molecules can ubiquitinate only a specific target protein upon activation.  Each E3 protein ligase can also only be activated through a specific signal such as phosphorylation, allosteric transition due to ligand binding, or protein subunit addition. This regulates the ubiquitination of the target protein leading to its degradation by the proteasome.  For example, APC, or anaphase-promoting complex, is a multi-subunit E3 ligase responsible for the degradation of important cell cycle regulators. However, it is only activated at specific time points during the cell cycle by the addition of co-activator subunits. These subunits play an important role in the selective binding of the APC to its target proteins.  Alternatively, a conformational change in the target protein itself upon phosphorylation of a specific site, or dissociation of a protein subunit, or cleavage of a peptide bond, can unmask a normally hidden degradation signal. This signal can then be recognized by a ubiquitin ligase, resulting in the protein’s ubiquitination.  For example, cyclin proteins contain an internal degradation signal which can only be recognized by APC. However, this signal is only exposed when a cyclin kinase phosphorylates a specific site in the cyclin protein. This brings about a conformational change in the protein that unmasks its degradation signal – leading to its polyubiquitinylation, and degradation in the proteasome.