Protein degradation pathway

Figure 2. Model-2. Parkin is linked to sporadic PD as well as AR-JP. a-Syn, a-synuclein. For details including environmental stress, neurotoxin, ROS, qualitycontrolling E3, UCH-Ll, CHIP, UPR, CDCrel-1, initiation , and promotion , see text. In this model, impairment of protein degradation pathway downstream of ubiquitination results in accumulation of ubiquitinated protein(s) and non-ubiquitinated protein(s), i.e., aggregate formation (LB). At present, it is unknown whether parkin is involved in LB formation or LB causes dopaminergic neuron death, however it is currently clear that LB formation is not directly linked to neuronal death and pathogenesis of PD as shown by a dotted line (see text). Note that AR-JP can also be explained by model-2, if parkin operates as a qualitycontrolling E3.

Since plastids have a limited set of protein degradation pathways, foreign proteins that exhibit harmful effects to the plant in the cytoplasm may be more stable when they accumulate within the chloroplast (Heifetz, 2000). For example, the vaccine protein cholera toxin B subunit was shown to be toxic even when it accumulated to very low levels within the plant cytoplasm, but was nontoxic when it accumulated to large quantities within the chloroplast. Plastids also possess the ability to form disulfide bonds, a requirement for many correctly folded mammalian proteins (Daniell et al., 2005a). These properties have made them attractive for the production of biopharmaceuticals in plants. 

B. Hazes and R. J. Read, Accumulating evidence suggests that several AB-toxins subvert the enoplasmic reticulum-associated protein degradation pathway to enter target cells, Biochemistry 36 11051-11054 (1997). 

W., Eds., The Proteosome-Ubiquitin Protein Degradation Pathway, Springer, Berlin, 2002 Saklatvala, J. and Nagase, H., Eds., Proteases and the Regulation of Biological Processes, Portland Press, London, 2003. 

Rubinsztein, D.C. 2006. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443 780-786. 

Varshavsky and colleagues have also characterized a nonlysosomal protein-degradation pathway in eukaryotic cells, primarily in yeast. In addition to confirming that the N-end rule applies to eukaryotic proteins as well, they identified a 76-amino-acid protein called ubiquitin as one of the major signals for protein degradation. Ubiquitin got its name because it is found in essentially every cell type ever examined. The sequence of ubiquitin is almost identical in yeast and humans,... 

Ubiquitin-dependent protein degradation pathway. ATP hydrolysis is required to attach ubiquitin to the carrier protein El, which then passes the ubiquitin moiety to the activating protein E2. The protein E3 recognizes the NH2-terminal residues and directs E2 to conjugate ubiquitin to lysine residues in the protein. 

The variety of protein degradation pathways and the necessity to demonstrate control present a significant analytical challenge to the manufacturers of protein drugs. Besides the traditional analytical tools of protein chemistry (gel... 

Vol. 268 ZwickI, Peter Baumeister, Wolfgang (Eds.) The Proteasome-Ubiquitin Protein Degradation Pathway. 2002, X, 213 pp. ISBN 3-540-43096-2... 

Tong, Y., Yamaguchi, H., Giaime, E., et al. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accirmulation of alpha-synuclein, and apoptotic cell death in aged mice. Proc. Natl. Acad. Sci. USA 107, 9879-9884 (2010). doi 10.1073/pnas.l004676107... 

Mosedale, M., Wu, H., Kurtz, C.L., SchmidL S.R, Adkins, K., Harrill, A.H., 2014. Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug. Toxicol Appl Pharmacol 280, 21-29. 

Asn and Asp residues are involved in the predominant protein degradation pathway, which is spontaneous nonenzymatic hydrolysis of the side chain via a succinimide intermediate " (Eigure 3). 

Simpson, J.C., Roberts, L.M., Romisch, K., et al., 1999. Ricin a chain utilises the endoplasmic reticulum-associated protein degradation pathway to enter the cytosol of yeast. FEBS Lett. 459 (1), 80-84. Oct 1, 1999. 

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