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Definition

One of the best studied responses to environmental stress is the heat shock response, which leads to increased expression of a highly conserved group of proteins, called heat shock proteins (Hsps).

 

Discovery

The enhanced synthesis of a few proteins immediately after subjecting cells to a stress such as heat shock was first reported for drosophila cells in 1974, and the universality of the response from bacteria to human was recognized shortly thereafter. Past several years, however, it has become apparent that Hsps are directly involved in the vital process of protein biogenesis. Because of this involvement, they have subsequently been termed ‘molecular chaperones’.

 

Structure
Hsps are named according to their approximate molecular mass, Hsp70s, Hsp60s and Hsp90s. The N-terminal two thirds of Hsp70s are more conserved than the C-terminal third. Hsp70 bind to ATP with high affinity and possess a weak ATPase activity which can be stimulated by binding to unfolded proteins. ATP binding activity resides in an N-terminal fragment of 44 kDa which lacks the peptide binding capacity, indicating that the ability to bind polypeptides resides within the C-terminal half. The structure of this ATP binding domain shows many hallmarks of nucleotide binding proteins. It consists of two lobes forming an ATP-binding cleft1.

 

Hsp60 proteins are abundant proteins found in all bacteria, mitochondria and plastids of eukaryotic cells. They have a characteristic oligomeric structure usually consisting of 14 subunits of approximately 60 kDa each arranged in two heptametrical rings stacked on top of each other1.

 

The Hsp90 family of heat-shock genes is the third major. Biochemical studies demonstrated that cytosolic hsp90s of vertebrates associate with a variety of cellular proteins including cellular tyrosine kinases, steroid hormone receptors, actin and tubulin. Studies on the interaction of Hsp90 with steroid hormone receptors in vertebrates and yeast have revealed that in the absence of steroid hormones, the receptor is complexed to Hsp90 and a variety of other proteins in a 300 kDa aporeceptor. Upon hormone binding, Hsp90 dissociates from the receptor which in turn binds to DNA as a transcriptional activator1.

 

Mechanism of action
The induction of Hsps by heat and other types of stress is mediated by the heat shock transcription factor (HSF).  Transcription of heat shock protein genes is under the control of a family of heat shock transcription factors (HSF), which bind to heat shock elements (HSE; inverted repeats of the pentameric sequence nGAAn) in the promoter regions of these genes. The presence of this element located about 80-150 base pairs upstream of the start site of RNA transcription is the most definitive evidence that the gene encodes a heat shock protein. In higher eukaryotes, the factor is not normally bound to the DNA but does so rapidly after stress, and additional phosphorylation of them factor is detected2.

 

The events regulating heat shock gene expression in the prokaryote differ in several respects. First, unlike the eukaryote where different heat shock genes are expressed noncoordinately, heat shock genes in the prokaryote form a regulon and appear simultaneously. Second, the heat shock transcription factor is an isomer of the s subunit, the regulatory element in the bacterial RNA polymerase. This s factor exists at low levels under normal growth conditions, but levels rise quickly after heat shock 2.

 

Functions
Stress-induced activation of the heat-shock response: Since Hsps are expressed by cells under conditions such as increased temperature, oxidative stress, nutritional deficiencies, exposure to UV light and chemicals, viral infection, emotional and mechanical stress. Consequently, they are also referred to as stress proteins and their upregulation is sometimes described more generally as part of the stress response3.

 

Hsps as molecular chaperones: Hsps proteins act as molecular chaperones through their ability to refold polypeptides with an altered conformation. Moreover, constitutive hsps homologues have been characterized that participate in the folding of newly made polypeptides, in the assembly of protein complexes in the endoplasmic reticulum, in the translocation of polypeptides through membranes or in masking mutations that alter protein folding4.

 

Hsps in cytoprotective and tumor therapy: Hsps have a dual function depending on their intracellular or extracellular location. Hsp90, Hsp70 and Hsp27 can directly interact with different proteins of the tightly regulated programmed cell death machinery and thereby block the apoptotic process at distinct key points. In cancer cells, the expression of Hsp27, Hsp70 and/or Hsp90 is frequently abnormally high, they participate in oncogenesis and in resistance to chemotherapy. Therefore, the inhibition of Hsps has become an interesting strategy in cancer therapy. In contrast to intracellular Hsps, extracellular located or membrane-bound Hsps mediate immunological functions5.

 

Hsp and the Immune Response
Hsps are immunodominant molecules, and a significant element of the immune response to pathogenic microorganisms is directed toward Hsp-derived peptides. Phylogenetic similarity between microbial and mammalian forms of these molecules (is 50% to 60% identical residues in the case of the hsp60 family), and it has prompted debate as to whether hsps might also act as potentially harmful autoantigens. The proposition that immunologic recognition of cross-reactive Hsp epitopes might provide a link between infection and autoimmunity has been supported by studies implicating immunity to hsps in arthritis, multiple sclerosis, and diabetes6.

 

 

References

 

1.     Becker J and Craig EA (1994). Review Heat-shock proteins as molecular chaperones. Eur. J. Biochem., 219, 11 -23.

2.     Schlesinger, MJ (1990). "Heat shock proteins". J Biol. Chem., 265 (21): 12111–12114.

3.     Cotto JJ and Morimoto RI (1999).Stress-induced activation of the heat-shock response: cell and molecular biology of heat-shock factors. Biochemical Society Symposion., 64: 105-118

4.     Arrigo AP (2005). Heat shock proteins as molecular chaperones. Med. Sci. (Paris), 21(6-7):619-25.

5.     Didelot C, Lanneau D, Brunet M, Joly AL, De Thonel A, Chiosis G, Garrido C (2007). Anti-cancer therapeutic approaches based on intracellular and extracellular heat shock proteins. Curr. Med. Chem. 14(27):2839-47.

6.     Lamb JR, Bal V, Mendez-Samperio A, et al (1989). Stress proteins may provide a link between the immune response to infection and autoimmunity. Int. Immunol., 1: 191–196.

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