Chaperones identification

Brodsky JL, Chiosis G (2006) Hsp70 molecular chaperones emerging roles in human disease and identification of small molecule modulators. Curr Top Med Chem 6 1215-1225... 

Santhoshkumar, P., and Sharma, K.K. (2002) Identification of a region in alcohol dehydrogenase that binds to ot-crystallin during chaperone action. Biochim. Biopbys. Acta 1589, 115-121. 

Ballinger, C. A., P. Connell, Y. Wu, Z. Hu, L. J. Thompson, L. Y. Yin, and C. Patterson. Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol. 19 4535-45.1999. 

Sequence Comparisons Proteins called molecular chaperones (described in Chapter 4) assist in the process of protein folding. One class of chaperone found in organisms from bacteria to mammals is heat shock protein 90 (Hsp90). All Hsp90 chaperones contain a 10 amino acid signature sequence, which allows for ready identification of these proteins in sequence databases. Two representations of this signature sequence are shown below. 

A. Genetics and Chemistry 1. Identification of Yeast Atxl as a Copper Chaperone... 

Considerable progress has been made toward the elucidation of the function of Cox 17 since its identification 5 years ago. It has been shown to be a copper-containing protein that is essential for assembly of the cytochrome c oxidase complex and is present in both the mitochondria and the cytosol. These features are strongly indicative of a copper chaperonelike function. It appears that Cox 17 interacts directly with Scol and Sco2, but the delineation of the remainder of the copper-trafficking pathway from the chaperone to the cytochrome c oxidase complex remains unclear. It is also unclear exactly how Cox 17 binds copper, since the CCXC motif is unique to date. If it binds three copper atoms with only three cysteine residues, the coordination of the metal ions will be extremely interesting, and elucidation of the protein structure will undoubtedly yield new insights into copper transportation in the cell. 

The identification of a thio-ether bond in the active site of GOase (Ito et al., 1991) immediately encouraged speculation about its biogenesis. Is the formation of this bond autocatalytic as appears to be the case with the TPQ cofactor in amine oxidases (Dooley, 1999) or does it require chaperones as is the case in the biogenesis of the TTQ cofactor (Christoserdov et al., 1991) Does biogenesis of the thioether bond involve radicals There are... 

Brough PA, Barril X, Borgognoni J et al (2009) Combining hit identification strategies fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J Med Chem 52 4794—4809... 

The previous section looked at examples in which detailed analysis of specific proteins identified as targets of the heat shock response has led to the identification of new molecular chaperones as well as an expanded view of the requirements for efficient protein production and folding. In this section we focus on how the use of DNA microarrays has provided a global view of the spectrum of targets of a specific stress response, the unfolded protein response (UPR), which plays a critical... 

CoLPAS GJ, Beayman TG, Ming LJ and Hausingee RP (1999) Identification of metal-binding residues in the Klebsiella aerogenes urease nickel metcdlo-chaperone, Ure E. Biochemistry 38 4078-4088. 

---