Protein folding in the cell

Gething, Mary‐Jane; Sambrook, Joseph

doi:10.1038/355033a0

Cited by 4,010 publications

(2,327 citation statements)

References 186 publications

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“…The association of the E. coli GST-related protein SSPA with the RNA polymerase holoenzyme (Ishihama & Saitoh, 1979) may be another example of a noncovalent, GST-containing complex. In a very general sense, it may be conjectured that GST domains facilitate protein folding and assembly in a chaperonelike manner (Gething & Sambrook, 1992). A recent dramatic example of the possible chaperone-like activity in a GSTTrelated protein includes yeast protein URE2 that appears to undergo an autocatalytic, inheritable conformational change, in analogy to mammalian prion proteins (Weissmann, 1994;Wickner, 1994).…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic translation elongation factor 1γ contains a glutathione transferase domain—Study of a diverse, ancient protein super family using motif search and structural modeling

et al. 1994

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Using computer methods for multiple alignment, sequence motif search, and tertiary structure modeling, we show that eukaryotic translation elongation factor ly (EFly) contains an N-terminal domain related to class 0 glutathione S-transferases (GST). GST-like proteins related to class 8 comprise a large group including, in addition to typical GSTs and EFly, stress-induced proteins from bacteria and plants, bacterial reductive dehalogenases and P-etherases, and several uncharacterized proteins. These proteins share 2 conserved sequence motifs with GSTs of other classes (a, p, and K). Tertiary structure modeling showed that in spite of the relatively low sequence similarity, the GST-related domain of EFly is likely to form a fold very similar to that in the known structures of class a , p , and ?r GSTs. One of the conserved motifs is implicated in glutathione binding, whereas the other motif probably is involved in maintaining the proper conformation of the GST domain. We predict that the GSTlike domain in EFly is enzymatically active and that to exhibit GST activity, EFly has to form homodimers. The GST activity may be involved in the regulation of the assembly of multisubunit complexes containing EFl and aminoacyl-tRNA synthetases by shifting the balance between glutathione, disulfide glutathione, thiol groups of cysteines, and protein disulfide bonds. The GST domain is a widespread, conserved enzymatic module that may be covalently or noncovalently complexed with other proteins. Regulation of protein assembly and folding may be 1 of the functions of GST.

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Section: Discussionmentioning

confidence: 99%

Eukaryotic translation elongation factor 1γ contains a glutathione transferase domain—Study of a diverse, ancient protein super family using motif search and structural modeling

et al. 1994

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“…4,[8][9][10] A more complete knowledge of the behaviour of proteins in the cell has, however, been limited by the challenges involved in defining the structures of native states in complex environments and of the highly dynamic structural ensembles that describe most of the additional forms of proteins that are now known to be of biological importance, including natively unfolded states and partially folded states involved in folding and in aggregation.…”

Section: Multiple Forms Of Protein Structurementioning

confidence: 99%

“…In order to function, the large majority of our proteins need to fold into a specific three-dimensional structure. 4,[8][9][10] Indeed, the wide variety of highly specific structures that results from protein folding, and which serve to bring key functional groups into close proximity, has enabled living systems to develop astonishing diversity and selectivity in their underlying chemical processes by using a common set of just twenty building blocks-the amino acids. 11 Much research has addressed the fundamental mechanism of protein folding through a combination of in vitro and in silico studies, and we now have considerable understanding at a molecular level of the fundamental principles underlying this complex process.…”

Section: Introductionmentioning

confidence: 99%

Quantitative approaches to defining normal and aberrant protein homeostasis

Vendruscolo

2009

Faraday Discuss.

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Protein homeostasis refers to the ability of cells to generate and regulate the levels of their constituent proteins in terms of conformations, interactions, concentrations and cellular localisation. We discuss here an approach in which physico-chemical properties of proteins and their environments are used to understand the underlying principles governing this process, which is crucial in all living systems. By adopting the strategy of characterising the origins of specific diseases to inform us about normal biology, we are bringing together methods and concepts from chemistry, physics, engineering, genetics and medicine. In particular, we are using a combination of in vitro, in silico and in vivo approaches to study protein homeostasis through the analysis of the effects that result from its perturbation in a select group of specific proteins, from either amino acid mutations, or changes in concentration and solubility, or interactions with other molecules. By developing a coherent and quantitative description of such phenomena, we are finding that it is possible to shed new light on how the physical and chemical properties of the cellular components can provide an understanding of the normal and aberrant behaviour of living systems. Through such an approach it is possible to provide new insights into the origin and consequences of the failure to maintain homeostasis that is associated with neurodegenerative diseases, in particular, and the phenomenon of ageing, in general, and hence provide a framework for the rational design of therapeutic approaches.

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“…Molecular models suggest that hsp70 proteins form complexes with other polypeptides by interacting with putative hydrophobic domains in the latter (Flynn et al, 1991). In the presence of ATP, which binds to a pocket in a major domain of the hsp70 (Flaherty et al, 1990), the complex dissociates, allowing the protein to properly fold to a functional and, frequently, oligomeric form localized to a specific compartment of the cell (Craig, 1990;Gething & Sambrook, 1992). Based on our results described here and those of others, we propose that the nascent polypeptide of HSF, alone, could sense a stress such as heat shock.…”

mentioning

confidence: 99%