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The thesis examines in detail the folding and unfolding processes of a number of proteins including hb SBD, DDLNF4, single and multi Ubiquitin.
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.
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.
Defects in ubiquitin-dependent proteolysis have been shown to result in a variety of human diseases, including cancer, neurodegenerative diseases, and metabolic disorders.
The SCF (Skp1-Cullin-F-box-Hrt1) complex is a heteromeric ubiquitin ligase that multiubiquitinates proteins important for signal transduction and cell cycle progression.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.By proximity-dependent biotin identification (Bio ID), co-immunoprecipitation, and proximity-ligation assay (PLA), I identified the heat shock proteins HSC/HSP70 and HSP90 as novel Ch AT protein-interactors that are enriched in cells expressing mutant P17A/P19A-Ch AT.Pharmacological inhibition of these HSPs by treatment with the HSC/HSP70 inhibitors 2-phenylethynesulfonamide (PES) or VER-155008, or the HSP90 inhibitor 17-AAG reduced cellular Ch AT activity and solubility, and enhanced ubiquitination and proteasomal loss of Ch AT protein.The cooperativity of denaturation transition was investigated using lattice and off-latice models.Our studies reveal that the sharpness of the transition enhances as the number of amino acids grows.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. 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 .