Ubiquitin function

Proteosomal degration is the process by which improperly folded proteins or proteins with altered post-translational modifications are removed from a cell before they have a detrimental effect on cellular function. This is performed in small organelles known as proteosomes. Proteins are targeted for destruction in the proteosome by having a number of small ubiquitin molecules added. 

Ubiquitin/Proteasome. Figure 2 Functional consequences of ubiquitin linkage. Substrates (blue bars) are linked via lysine residues (K) to ubiquitin or ubiquitin chains, (a) Attachment of chains connected via Lysines in position 48 of ubiquitin (K48) targets substrates for proteasomal degradation. In contrast modification of one (b) or multiple (c) lysines by a single ubiquitin molecule mediates novel protein interactions or initiates endocytosis. Conjugation of K63-linked polyubiquitin (d) alters protein function and can also serve as a signal for endocytosis. 

In concordance with the central role of ubiquitin modification in multiple cellular functions perturbations of this system are associated with a variety of diseases. Defects in the control of cell cycle regulators by the ubiquitin proteasome system are connected to cancer progression and many E3 ligases were originally identified as oncogenes. 

As the ubiquitin proteasome pathway is a main route for protein clearance it is not surprising that in protein-opathies (disease caused by aggregate prone proteins) like sporadic Parkinson- or Huntington disease proteasome activity is reduced. Autosomal recessive loss of function of the E3 ligase parkin is the molecular base for one of the most common forms of familial Parkinson disease. 

In Cystic fibrosis a point mutation of the cystic fibrosis transmembrane regulator (CTFR) prevents transport of this molecule to the cell surface. Instead this otherwise functional molecule is degraded by the ERAD-ubiquitin proteasome pathway. 

Mukhopadhyay D, Riezman H (2007) Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315 201-205... 

Fig. 2.5.5 A study examining the conformational changes of the protein ubiquitin, showing the population ratio of the A-state to the native-state as a function of time, (a) The reaction from 0 to 120 s. (b) The reaction for the first 40 s, including curves fit to a single exponential. Reprinted with permission from Ref. [37]. Copyright (2003) American Chemical Society.

Figure 1. The cell cycle as a Cdc2 cycle. Progression through the eukaryotic cell cycle is sensitive to the phosphorylation state of Cdc2. A block to DNA synthesis (S) prevents dephosphorylation, and hence activation, of Cdc2. Impaired spindle function will prevent deactivation of Cdc2 and thus blocks exit from M phase (Hoyt et al., 1991 Li and Murray, 1991 reviewed in Nurse, 1991). Exit from M phase requires destruction of the regulatory subunit, Cyc B. Dephosphorylation of Cdc2 at thr-161 may act to destabilize the Cdc2/Cyc B complex and thus allow the ubiquitination of Cyc B followed by its destruction.

Fig. 11 (a) 2D NCO experiment with optimal control element inserted for 15N — 13C transfer. Transfer efficiencies for the ocNCO experiment optimized for 12 kHz spinning speed as function of (b) resonance offsets for 13C and 1SN and (c) rf inhomogeneity/adjustment in terms of scaling factors on the nominal rf field strengths for 13C and 15N. (d) Experimental ocNCO 2D spectrum of uniformly 13C,15N-labeled ubiquitin with the projections to the left comparing ocNCO experiment most intense) and DCP (less intense) based NCO experiments [reproduced with permission from [161] (a, d) and [164] (c)]... 

Robust decreases in the expression of the various proteasome subunits and ubiquitin-conjugating enzymes have been described in prefrontal cortex in schizophrenia. Neuronal ubiquitin and proteasomes play an important role in the assembly, function and plasticity of the synapse. Structural proteins including tubulin and a-spectrin also show decreased expression in prefrontal cortex. 

PTMs are important for the regulation of protein function and the maintenance of cellular hemostasis. There are 300 or more reported PTMs of proteins. PTMs may involve the addition of functional groups such as acetyls in acetylation, hydroxylation, amidation, and oxidation or the addition of peptides or proteins such as ubiquitination, SUMOylation (addition of small ubiquitin-like modifier), and ISGylation (addition of interferon-stimulated gene15). 

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