Chaperones function

A nonsubstrate protein that interacts specifically with a molecular chaperone, and is important for efficient chaperone function. 

Hsp90 is a molecular chaperon required for the refolding of proteins in cells exposed to environmental stress. It contains an ATP-binding pocket in its amino terminus. Several natural products, for example radicicol (230) (Scheme 48), bind to this pocket and inhibit its chaperon function, which is mirrored in enhanced proteosomal degradation of Hsp90 client proteins, so that compounds like 230 are of interest as novel anticancer agents. 

Figure 12.2 Copper chaperone function, (a) Copper homeostasis in Enterococcus hirae is affected by the proteins encoded by the cop operon. CopA, Cu1+-import ATPase CopB, Cu1+-export ATPase CopY, Cu1+-responsive repressor copZ, chaperone for Cu1+ delivery to CopY. (b) The CTR family of proteins transports copper into yeast cells. Atxlp delivers copper to the CPx-type ATPases located in the post Golgi apparatus for the maturation of Fet3p. (c) Coxl7p delivers copper to the mitochondrial intermembrane space for incorporation into cytochrome c oxidase (CCO). (d) hCTR, a human homologue of CTR, mediates copper-ion uptake into human cells. CCS delivers copper to cytoplasmic Cu/Zn superoxide dismutase (SOD1). Abbreviations IMM, inner mitochondrial membrane OMM, outer mitochondrial membrane PM, plasma membrane PGV, post Golgi vessel. Reprinted from Harrison et al., 2000. Copyright (2000), with permission from Elsevier Science.

The functions of the calcium-storage capacity of the ER are at least threefold the association of Ca2+ with Ca2+-binding proteins in the ER is part of a chaperone function that is essential for normal protein synthesis the rapid rate of Ca2+ uptake by endoplasmic pumps provides shortterm cytoplasmic Ca2+ buffering that resists untoward and transient changes in [Ca2+] and, finally, many signaling pathways employ elevated [Ca2+] to activate physiological processes. Extensive Ca2+ release from ER is coupled to activation of Ca2+ entry across the plasma membrane, a process known as capacitative calcium entry, which is discussed below. 

Moscinski L, Atadja P, Bhalla K (2004) Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res 10 4991 997 Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumarawsamy S, Boyapalle S, Atadja P, Seto E, Bhalla K (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280(29) 26729-26734 Bannister AJ, Schneider R, Kouzarides T (2002) Histone methylation Dynamic or static Cell 109 801-806... 

Atadja, P., Seto, E. and Bhalla, K. (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 a novel basis for antileukemra activity of histone deacetylase inhibitors. The Journal of Biological Chemistry, 280, 26729-26734. 

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. 

The chaperoning function of Hsp90 can be switched-off by inhibiting its ATP-ase activity [180,181]. 

Another mechanism of chaperone function involves entry of the unfolded protein into a... 

Figure 7.15. Functions of cold-shock proteins (Csp s) as RNA chaperones. The model shows how Csp s assist in coupling transcription to translation. Cold-shock proteins bind relatively weakly to nascent mRNA extending from the RNA polymerase complex (RNAP) and maintain the mRNA in a linear form that can be bound to ribosomes and translated into protein. Under nonstressful conditions, the weakly binding Csp s are present at adequate concentrations to perform this chaperoning function. However, during cold stress, the propensity for RNA to form secondary structures that block translation becomes greater. This necessitates that a higher level of Csp s be present in the cell, to ensure that chaperoning of mRNA is effective. (Figure modified after Graumann and Marahiel, 1998.)...

C. Regulation of Expression by Copper and Copper Chaperone Function... 

The copper chaperone function of Atxl was definitively demonstrated by O Halloran and colleagues in 1997 when they showed using electron paramagnetic resonance (EPR), X-ray absorption near edge structure (XANES), and extended X-ray absorption fine structure (EXAFS),... 

LeNaour, E., Brichory, E., Jang, J. H., Zhao, R., Puravs, E., Tea, J., Michael, C. W., Misek, D. E., Hanash, S. M. (2003). Global profiling of the cell surface proteome of cancer cells uncovers an abundance of proteins with chaperone function.. Biol. Chem. 278, 7607-7616. 

Wright CM, Chovatiya RJ, Jameson NE et al (2008) Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation. Bioorg Med Chem 16 3291-3301... 

Harrison, M. D., Jones, C. E., and Dameron, C. T., 1999, Copper chaperones function, structure and copper-binding properties, J. Biol. Inorg. Chem. 4 145fil53. 

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