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Most proteins are targeted to the 26S proteasome by covalent attachment of a multiubiquitin chain.A key component of the enzyme cascade that results in attachment of the multiubiquitin chain to the target or labile protein is the ubiquitin ligase that controls the specificity of the ubiquitination reaction.
The cellular loss of mutant Ch AT protein appears to be a result of increased proteasome-dependent degradation due to enhanced Ch AT ubiquitination.
Using a novel fluorescent-biorthogonal pulse-chase protocol, I determined that the cellular protein half-life of P17A/P19A-Ch AT (2.2 h) is substantially reduced compared to wild-type Ch AT (19.7 h), and that proteasome inhibition by MG132 treatment increases the half-life and steady-state levels of Ch AT protein.
It is currently unknown if this motif regulates Ch AT function.
In this thesis, I demonstrate that disruption of this proline-rich motif in mouse cholinergic SN56 cells reduces both the protein levels and cellular enzymatic activity of mutated P17A/P19A- and V18M-Ch AT.
Ch AT mutations are linked to congenital myasthenic syndrome (CMS), a rare neuromuscular disorder.
One CMS-related mutation, V18M, reduces Ch AT enzyme activity and cellular protein levels, and is located within a highly-conserved N-terminal proline-rich motif at residues .This peak can not be encountered by the Go models in which the non-native interactions are neglected.Our finding may stimulate further experimental and theoretical studies on this protein.Finally, cell-permeable Protacs can also promote the degradation of proteins in cells. s natural proteolytic machinery is a potential avenue for the treatment of human disease.Biologically, this work signifies the amazing versatility and flexibility of the ubiquitin-proteasome system. It was shown that refolding pathways of single Ubiquitin depend on what end is anchored to the surface.Namely, the fixation of the N-terminal changes refolding pathways but anchoring the C-terminal leaves them unchanged.We predict that, contrary to the AFM experiments, an additional unfolding peak would occur at the end-to-end $\Delta R \approx 1.5 $nm in the force-extension curve.Our study reveals the important role of non-native interactions which are responsible for a peak located at $\Delta R \approx 22 $nm.Protein degradation is one of the tactics employed by the cell for irreversibly inactivating proteins.In eukaryotes, ATP-dependent protein degradation in the cytoplasm and nucleus is carried out by the 26S proteasome.