Toxic protein aggregates

CD spectroscopy has also provided valuable insight into the chemical stability and chemical denaturation of proteins. A recent study by Rumfeldt etal. examines the guanidinium-chloride induced denaturation of mutant copper-zinc superoxide dismutases (SODs). These mutant forms of the Cu, Zn-SOD enzyme are associated with toxic protein aggregation responsible for the pathology of amyotrophic lateral sclerosis. In this study, CD spectroscopy was used in conjunction with tryptophan fluorescence, enzyme activity, and sedimentation experiments to study the mechanism by which the mutated enzyme undergoes chemical denaturation. The authors found that the mutations in the enzyme structure increased the susceptibihty of the enzyme to form partially unfolded destabilized monomers, rather than the stable metaUated monomer intermediate or native metallated dimer. 

Squire,J. (1981). The Structural Basis of Muscle Contraction. Plenum Press, New York. Stefani, M., and Dobson, C. M. (2003). Protein aggregation and aggregate toxicity New insights into protein folding, misfolding diseases and biological evolution. J. Mol. Med. 81, 678-699. 

Bucciantini, M., Giannoni, E., Chiti, F., Baroni, F., Formigli, L., Zurdo, J., Taddei, N., Ramponi, G., Dobson, C. M., and Stefani, M. (2002). Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416, 507-511. 

The biosynthesis of L-Trp from CHA is outlined in Fig. 8.16. The complex transformation of CHA into phosphoribosyl anthranilate (PRAA) is, in E. coli and C. glutamicum, catalyzed by a protein aggregate that is inhibited by the l-Trp end product. The final two steps are performed by a single protein indole, which is toxic to the cell, is channeled directly into the active site where the fi-... 

A characteristic feature of all the Q -expansion diseases is the presence of insoluble protein aggregates (inclusion bodies) in the affected brain regions. Some authors have suggested that these insoluble aggregates are toxic and thereby contribute to the disease process (e.g., Bates, 2003). However, other studies indicate that the insoluble aggregates per se may not be toxic (e.g., Saudou et al., 1998 Kuemmerle... 

Lovestone S, McLoughUn DM (2002) Protein aggregates and dementia is there a common toxicity J Neurol Neurosurg Psychiatry 72 152-161 Mandelkow EM, Schweers O, Drewes G, Biemat J, Gustke N, Trinczek B et al (1996) Structure, microtubule interactions, and phosphorylation of tau protein. Ann N Y Acad Sci 777 96-106 Mandell JW, Banker GA (1996) A spatial gradient of tau protein phosphorylation in nascent axons. J Neurosci 16 5727-5740... 

Bucciantini M, et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 2002 416 507. 

Sakahira H, Breuer P, Hayer-Hartl MK, Hai ti FTJ (2002) Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc Natl Acad Sci USA 99(Suppl 4) 16412— 16418. 

At the beginning there seemed to be no common feature to all these diseases, but since about 1963 the fact that protein aggregates could be found in a wide variety of neurodegenerative diseases gained recognition, when Orgel presented the thesis, that accumulated proteins lead to senescence of cells through toxic accumulation. [4,23]. 

However, most often, aggregation is not desired. The presence of a nonnative aggregate is a cause of concern to biopharmaceutical scientists because this aggregate may have altered activity, clearance, and toxicity compared with the native protein. Aggregates of ribonuclease A were found to be less active. " Covalent aggregates of insulin resulted in the appearance of antibodies to the protein in the blood of insulin-using diabetic patients. ... 

---