Heat Shock Proteins
- Function and Role -


What are Heat Shock Proteins and what are their function?
 Heat Shock Proteins/ Molecular Chaperones : Descriptive
Protein folding and the role of molecular chaperones (brief breakdown)
 Diagram demonstrating Role of Heat Shock Protein
Role of HSP Continued
 Table: HSPs and their Function
 Heat Shock Proteins: Human Immune Response
References
Miscellaneous: Heat Shock Proteins and Disease
Sample Mechanism for HSPs used in Cancer Treatment

 

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The diagram shows the role of heat-shock proteins and a chaperonin in protein folding. 

As the ribosome moves along the molecule of messenger RNA, a chain of amino acids is built up to form a new protein molecule. 

The chain is protected against unwanted interactions with other cytoplasmic molecules by heat-shock proteins and a chaperonin molecule until it has successfully completed its folding. [6]

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 Heat shock proteins (Hsp) comprise a group of ubiquitous polypeptides whose expression is induced when cells are subjected to stressful conditions such as: increasing temperatures
high pressures, or toxic compounds [3].
The induction of Hsp correlates with the abundance of unfolded polypeptide chains, which suggest a protective physiological role for these proteins [3].
Their activity involves a chaperone-like behavior that helps the correct folding of nascent polypeptide chains by binding to exposed hydrophobic residues. 
Hsp are involved in the assembly and disassembly of multimeric protein structures, the translocation of proteins across membranes, and the secretion and degradation of proteins [3].
Hsp also stimulate protein glycosylation. Although the stress response is well documented in a wide range of organisms, its regulation and molecular mechanism are presently not very clear [3].

 

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Heat Shock Proteins: Human Immune Response
        - Antigenics : Pioneers in therapeutic use of Heat Shock Proteins

Heat shock proteins stimulate a diverse immune response [1].

http://www.antigenics.com/tech/fingerprint.html

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 HSPs and their Function [4]
 

Heat Shock Protein
Cohorts
Function, etc.
Hsp100
?
ATPse; dissociates aggregates, facilitates proteolysis; essential in yeast for acquired thermotolerance; essential for yeast prion propagation
Hsp90
Immunophilins, Hsp70, others
stabilizes proteins prior to complete folding or activation; forms stable complexes with inactive glucocorticoid receptor and other transcription factors; most abundant non-ribosomal protein (cytosolic version); most abundant protein in endoplasmic reticulum (ER version)
Hsp70
Hsp40
ATPase; stabilizes proteins prior to complete folding, transport across membranes and proteolysis; found associated with misfolded and unassembled proteins, e.g., mutant p53 in cytosol or immunoglobulin heavy chains in ER of cells that don't make light chains; homologs in mitochondria and chloroplasts
Hsp60
Hsp10
ATPase; promotes efficient folding; only in mitochondria and chloroplasts of eukaryotes; distant homolog in cytosol is specialized for folding actin and tubulin; a.k.a., chaperonin
Hsp25
?
blocks aggregation; involved in regulation of actin assembly/disassembly

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  • The primary determinant of folded protein structure is the amino acid sequence and some proteins can spontaneously fold or refold to a functional conformation. 
  • Other proteins require assistance to fold correctly and this is provided by a family of proteins known as molecular chaperones that have been highly conserved in evolution [5]
  • Chaperones are involved at all stages of cellular metabolism - during protein synthesis, membrane translocation, protection from environmental denaturants and in targetting proteins for degradation and immune display.
  • The exposed polypeptides are not subject to possible protein aggregation. This can be harmful to the cell its self. 
  • To prevent this aggregation from occurring, chaperones such as HSPs bind to the exposed sites and protect them by helping refolding the protein into a more kinetically stable structure. (Heat Shock Proteins bind to denatured proteins to prevent aggregation) [4].
  • However, it does not necessarily catalyze the steps it takes to fold the protein, instead a chaperone corrects misfolding or prevents it from occurring. 
  • The chaperone works by guiding the folding process; it attaches to the protein and slows down the process of folding, decreasing the likely hood of an incorrectly folded structure [5].
  • Some Heat Shock Proteins have the ability to rescue already aggregated proteins.

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The purpose of activating HSPs is to protect the cell from the environmental stress. Another role of HSP is to act as
chaperone proteins  [8]. These proteins will bind to proteins that have been newly transcribed and help facilitate there folding [8]. By doing this they ensure that new proteins fold into the proper conformation. Also realizing this ability can be used in time of increased temperature when a functioning protein may be denatured [8]. The HSP will function as a chaperone by either facilitating the protein back to its proper conformation or if the damage is irreparable, then the protein is targeted for destruction. The destruction of these proteins can be  accomplished by  protease function of HPSs that have thisfunction. This mechanism shows how the HSPs can be regulated by amounts of misfolded proteins [8].

 

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Heat Shock Proteins and Disease [4]
Viral infection induces Hsp expression. Bacterial viruses use Hsps to facilitate takover of the cellular DNA
     replication machinery, and they employ Hsps for assembly of virus particles. In eukaryotes, heat shock proteins associate
     with key viral products, such as simian virus 40 (SV40) T-antigen, that control cell cycle progression and cause tissue
     transformation (cancer).
     Oxidative stress induces Hsp expression. Immune cells release nitric oxide and superoxide in the attack on invading
     cells. Host cells express Hsps to protect against oxidative damage. Unfortunately, the pathogens also mount a protective
     response with massive overproduction of Hsps.
     Hsp70 conveys peptide antigens for presentation to the immune system. Similar to its role in delivery of
     newly-synthesized proteins to the mitochondrion and ER, Hsp70 delivers peptides to the endoplasmic reticulum and
     proteins to the lysosome. Peptides generated by the proteasome in the cytoplasm are transported through the ER
     membrane via TAP transporters, loaded into class I major histocompatibility (MHC) proteins, and presented to CD8
     cytotoxic T-cells. Peptides generated by acid hydrolases in the lysosomes are loaded into class II MHC proteins and
     presented to CD4 helper T-cells.
     Hsps are immunodominant antigens. Since they are so abundantly expressed, Hsps swamp the immune system with
     epitopes. Despite that they are highly conserved proteins, sufficient sequence divergence allows the mammalian immune
     system to avoid tolerance of Hsps. In some cases, anti-Hsp responses are protective. In other cases, anti-Hsp responses
     are thought to initiate or propagate autoimmune disease by cross-reacting with self Hsps. In still other cases, a response
     against self Hsp (Hsp60) paradoxically suppresses autoimmune disease symptoms!
     Emotional as well as mechanical stresses induce Hsp expression. When rats are physically restrained, their
     vascular endothelial cells express elevated levels of Hsp70. The response has been linked to an abrupt increase in blood
     pressure. Elevated Hsp70 expression protects against cardiac failure. Hearts of transgenic mice that express elevated
     Hsp70 sustain less damage as a result of an experimental ischemic event.
     Hsp100 is necessary for propagation of prions in yeast. Aggregates of the Sup35 protein propagate themselves in a
     reaction that depends on yeast Hsp100. Although mammalian prions are composed of an unrelated protein, experiments
     with transgenic mice suggest that the species barrier is at least partly imposed by interactions between the prion proteins
     and a host factor that could be a molecular chaperone.
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 (adapted from ref. "U Jakob").

Working model for the dynamic and transient interactions of progesterone
 receptor with the Hsp90 superchaperone complex
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Developments in the area of HSPs discovered a group of proteins called chaperones (or chaperonins) that are associated with the target protein during part of its folding process.However, once folding is complete (or even before) the chaperone will leave its current protein molecule and go on to support the folding of another [2].
Proper folding of some proteins appears to call for not just one chaperone, but several. Especially clear evidence for suchmulti-step chaperoning is provided by test-tube experiments on a protein known as rhodanese. Proper folding of this protein, the experiments show, requires five different chaperone-type proteins acting at two distinct steps in the operation [2]. Early in the folding process, rhodanese binds to a chaperone known as DnaK; the complex that binds a further chaperone: DnaJ. Somewhat later, a protein known as GrpE catalyzes transfer of the partially folded rhodanese to another chaperone, GroEL, and its partner, GroES. These latter two proteins then see rhodanese all the way through to its properly folded state [2].
Several lines of evidence suggest that chaperones' primary function may be to prevent aggregation [2].For example, a chaperone found in the `power plant' organelles of mammalian cells (but otherwise similar to GroEL) has been shown to consist of 14 protein chains arranged as two doughnuts stacked on top of each other (see figure). The chaperoned protein sits inside the two doughnut holes, safely sequestered from other molecules with which it might aggregate [2].
A role for chaperones in preventing aggregation is also suggested by what happens to mammalian proteins produced in
bacteria. Although bacteria have chaperones, they are not the same as those in mammals [2]. It is thus easy to imagine that they may be relatively ineffective toward mammalian proteins, and that this results in the aggregation so often seen. Indeed, there has been one case in which bacteria engineered to overproduce their own chaperones successfully produced a mammalian protein that otherwise irretrievably aggregated [2]. Unfortunately, this approach has failed in other cases. And no one has yet reported introduction of mammalian chaperones into bacteria to help produce soluble mammalian proteins. Yet this, along with the introduction of mutations that block the aggregation pathway and the discovery of small molecules that prevent aggregation, is one of the most promising ways to overcome the roadblocks that biotechnology companies have so often encountered [2].

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References:

[1] Antigenics: Definition of Heat Shock Protein
           http://www.antigenics.com/tech/why.html

[2] Attfield, Derrick, Kinzler, Donna, Zavoral, Tom and Tahara, Hideaki. Basic Science:
           Heat-Shock Proteins - Emerging keys to unlock the secret of the allo and tumor immune responses. Vol. 4, No.1
           http://www.pci.upmc.edu/Internet/davis/ivv/Jan96/hsp.html.  January 1996.

[3] Compadre, R. Lilia Ph.D., Henle, Kurt Ph.D., Byrd, Chrystine UAMS, Murthy,
                Krishna Ph.D., Joachimiak, Andrzej Ph.D., Structure-Function of Heat Shock Proteins.
           http://www.uark.edu/staff/arknet/internet2/grant-uams-appl13.html.

[4] Dr. Landry <landry@mailhost.tcs.tulane.edu> Protein Interactions and Molecular Chaperones.
                Available: http://www.tulane.edu/~biochem/med/hsp.htm. 11 September 1998.

[5] Matthias, Gaestel. Small Heat Shock Proteins and Stress-Dependent Signal Transduction.
                Research Report 1996/97. Available: http://www.mdc-berlin.de/research/s72-73.htm#Top1.
                4 August 1998.

[6] Nurse Minerva. Chaperoneshttp://www.nurseminerva.co.uk/chaperon.htm  .
                11 November 1998.

[7] Tamura Y et al. Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations.
                Science 278, 117-120, 1997.

[8] Unknown Author. Heat Shock Regulon and Proteins. Available: http://web.utk.edu/~zeus.
                22 April 1999.

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