Ubiquitin/proteasome pathway

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. 

Mehle A, Strack B, Ancuta P, Zhang C, McPike M, Gabuzda D (2004) Vif overcomes the innate antiviral activity of APOBEC3G by promoting its degradation in the ubiquitin-proteasome pathway. J Biol Chem 279(9) 7792-7798... 

The following also points to a dysregulation of the ubiquitin-proteasome pathway as an important aspect of PD pathogenesis rare mutations in ubiquitin car-boxy-terminal hydrogenase LI (UCH-L1) associated with autosomal dominant PD in a German family [120], a UCH-L1 polymorphism associated with the develop-... 

At least three distinct forms of the IP3-R have been identified, and these share an overall amino acid homology of 60-80%. Type I predominates in the cerebellum and has been most extensively studied. It is the largest of the 3 forms of the receptor and, unlike type II and III receptors, the gene possesses a 120 nucleotide insert. Type II IP3-Rs are found mainly in non-neural tissues, whereas type III receptors occur in both neural and non-neural tissues. In response to chronic activation, IP3-Rs are degraded via the ubiquitin-proteasome pathway [14] (see also Ch. 2). 

Aviel, S., Winbeeg, G., Massucci, M. and CiECHANOVEE, A. Degradation of the Epstein-Barr virus latent membrane protein 1 (LMPl) by the ubiquitin-proteasome pathway targeting via ubiquitination of the N-terminal residue. J. Biol Chcm.,... 

Biederer, T., Volkwein, C., and Sommer, T. Degradation of subunits of the Sec61p complex, an integral component of the ER membrane, by the ubiquitin-proteasome pathway. EMBOJ. 1996, 35, 2069-76. 

Chen, Z. et al. Signal-induced site-specific phosphorylation targets 1 kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev 1995,... 

Wing, S. S. Deubiquitinating enzymes - the importance of driving in reverse along the ubiquitin-proteasome pathway, Int J Biochem Cell Biol, 2003, 35, 590-605. 

Fig. 9.1. Schematic representation of the ubiquitin-proteasome pathway. Ubiquitin moiecuies are activated by an El enzyme (shown green at 1 /3 scaie) in an ATP-dependent reaction, transferred to a cysteine residue (yeiiow) on an E2 or Ub carrier protein and subsequentiy attached to amino groups...

Palombella, V. f., Rando, O. f., Goldberg, A. L., and Maniatis, T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell 1994,... 

The ubiquitin-proteasome pathway is required for processing fh NF-kBl precursor protein and the activation of NF-kB. Cell 1994, 78, 773-785. 

ScHAUBER, C., Chen, L, Tongaon-KAR, L., Vega, I., Lambertson, D., Potts, W., and Madura, K. Rad23 links DNA repair to the ubiquitin/ proteasome pathway. Nature 1998,... 

Oxidized LDL alter cellular functions role in cell death Oxidized LDL seem to be poorly degraded by lysosomal enzymes and accumulate in lysosomes altering in turn their functionality (Dean et al., 1997). It has been proposed that inhibition of oxidized LDL degradation and subsequent lipid accumulation may induce a destabilization of the acidic compartment, and lysosomal rupture with a relocation of lysosomal enzymes in the cytosol (li W et al, 1998). This process, also called endopepsis , occurs early and could precede mitochondrial dysfunction and cell death (Lossel et al., 1994). Moreover, oxidized LDL trigger a dysfunction of the intracellular proteolytic ubiquitin/proteasome pathway (early activation followed by inhibition)... 

Vieira, O., EscargueU-Blanc, I., Jurgens, G Bomer, C, Almeida, L, Salvayre, R., and Negre-Salvayre, A., 2000, Oxidized LDLs alter the activity of the ubiquitin-proteasome pathway potential role in oxidized LDL-induced apoptosis, FASEB J. 14 532-542. 

The Ubiquitin-Proteasome Pathway and Endoplasmic Reticulum-Associated Degradation... 

Diseases Associated with the Ubiquitin-Proteasome Pathway 737... 

Diseases of the Nervous System Linked to the Ubiquitin-Proteasome Pathway 739... 

In the ubiquitin—proteasome pathway, the substrate proteins are marked by covalent linkage to ubiquitin for degradation by a proteolytic complex, the proteasome. 

Activation of ubiquitin by El requires ATP. El transfers the activated ubiquitin to an E2. Of the three classes of ubiquitin-conjugating enzymes (UBCs), El is the least physiologically regulated. In addition, because El activates ubiquitin, which is attached to all the substrates degraded by the ubiquitin-proteasome pathway, there is no substrate specificity in the action of this enzyme. E2s are more selective and believed to interact with specific E3s. Based on our knowledge of ubiquitination reaction, it can be asserted that E3 are the enzymes that possess substrate specificity. 

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