User talk:Mayanknkc

The heat-shock response is a widespread physiological phenomenon in all three domains of life and an attractive process for investigation of gene expression and regulation. Today it is well known that all organisms share a common molecular stress response that includes a dramatic change in the pattern of gene expression and the elevated synthesis of a family of stress-induced proteins called heat shock proteins (Hsps)

Discovery
The heat shock response was discovered in 1962 by F. Ritossa, who detected a new puffing pattern upon heat shock in the polytene chromosomes of the fruit fly, Drosophila melanogaster.

Introduction
Most proteins are relatively stable. Once made, they continue to perform their functions and are passed along at cell division. However, some proteins are less stable at elevated temperatures and tend to unfold. If we go beyond that range of temperature, the protein denatures, and the protein's function is lost. Improperly folded proteins are recognized by protease enzymes and are degraded. Thus it becomes evident that beyond a certain temperature, cells are under stress to maintain the structural integrity of the proteins in their systems or risk ending up in apoptosis. Consequently, cells that are heat stressed induce the synthesis of a set of proteins, the heat shock proteins that help counteract the damage. They are induced not only by heat, but also by several other stress factors that the cell can encounter. These include exposure to high levels of certain chemicals, and exposure to high doses of ultraviolet (UV) radiation.

Heat Shock Proteins
As mentioned in the previous section, heat shock proteins are proteins that are synthesized in response to elevated temperatures or other forms of stress. These proteins are highly conserved among all kinds of organisms, be it eukaryotes or prokaryotes. Heat shock proteins have two main functions, one is to prevent proteins from denaturing and the other is to degrade proteins that have lost their structural integrity. Heat shock proteins are primarily of two kinds each of which caters to one of the previously mentioned problem. The first types of heat shock proteins are called chaperones. As indicated by the name, these proteins help other proteins maintain their natural conformation even during adverse conditions. Hsp70 is a good example of such a protein. This is a highly conserved protein. Human Hsp70 is 73% similar to that in drosophila and 50% similar to the analogue of Hsp70 in E. coli, DnaK. The second type of heat shock proteins are those that aid in the degradation of denatured proteins. Ubiquitin is one of these proteins. Ubiquitin tags proteins that have lost their native conformation and results in them getting degraded.

The Hsp70 protein of E. coli, which is DnaK, prevents aggregation of newly synthesized proteins and stabilizes unfolded proteins. Major representatives of the Hsp60 and Hsp10 families in E. coli are the proteins GroEL and GroES, respectively. These are molecular chaperones that catalyze the correct refolding of misfolded proteins. Another class of heat shock proteins includes various proteases that degrade denatured or irreversibly aggregated proteins.

Regulation of Heat shock proteins
Despite the ubiquitous presence of the same protein in just about every living cell, the mechanisms by which the heat shock response is regulated very widely from organism to organism. In eukaryotes, transcriptional regulation is mediated by heat shock factors (HSFs) while in prokaryotes, it's achieved through control over the activity of the σ32 (sigma-32) factor. In yeast cells and E. coli, regulation of the response is only by transcription, while in drosophila; regulation is by both transcription and translation. This can be attributed to the longer life of mRNA in drosophila. Since mRNA doesn't degrade quickly in drosophila, translation of it has to be stopped to prevent unnecessary production of proteins.

Regulation in Prokaryotes
In prokaryotes, global control of the transcription of the genes coding for the Hsps (in the cytoplasm) is achieved through regulation of σ32 concentration. The fact that it’s a global control is because of the presence of a homologous sequence, the RpoH-box in all the Hsps. In the periplasmic space and cell envelope, expression of a different set of Hsps is achieved through RpoE.

σ32 is the first alternate sigma factor to be discovered in E. coli i.e., the RNA polymerase which binds to it can also bind to another sigma factor, σ70 and proceed with transcription. σ70 is the sigma factor which enables the transcription of most of the "housekeeping" genes of the cell. Since the same RNA polymerase binds to σ32 and σ70, high concentrations of σ32 will cause a higher fraction of the RNA polymerase to bind to σ32 than σ70. This will result in the repression of the "housekeeping" genes' transcription. The activity of σ32 is also regulated by negative feedback inhibition. Normally, the molecular chaperones which result from the activity of σ32, bind to σ32 and prevent it from completing it's function. The binding of the chaperones to σ32 might also trigger the degradation of σ32 by a metalloprotease.

However, under elevated temperatures, due to the accumulation of denatured proteins, the chaperones cease binding to σ32 letting it result in the formation of more and more heat shock proteins. And once the temperature comes back to normal, the chaperones return to binding with σ32 and inhibiting it or resulting in it's degradation.

Regulation in Eukaryotes
In eukaryotes, the heat shock transcription factors (HSFs) regulate the inducible Hsp expression. In response to various inducers such as elevated temperatures, oxidants, heavy metals, and bacterial and viral infections, most HSFs acquire DNA binding activity to the heat shock element (HSE), thereby mediating transcription of the heat shock genes, which results in accumulation of Hsps.

Homology
The heat shock proteins are ancient, having been identified in archaea too, and highly conserved. Molecular sequencing of heat shock proteins, especially Hsp70, has been used to help identify the phylogeny of eukaryotes. Heat shock proteins are present in all cells, although the regulatory system that controls their expression varies greatly in different groups of organisms. An interesting fact that is common about the genes coding for all the heat shock proteins is the lack of introns in them, even in the genes in higher organisms. Possibly, this is to ensure the speedy production of the heat shock proteins. The rapid synthesis of heat shock proteins in cells under stress emphasizes how important a role they play in surviving excessive heat, chemicals, or physical agents.

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