Heat shock protein
Encyclopedia
Heat shock proteins are a class of functionally related protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s involved in the folding and unfolding of other proteins. Their expression is increased when cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

 regulated. The dramatic upregulation
Downregulation and upregulation
Downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable...

 of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor
Heat Shock Factor
Heat shock factor , in molecular biology, is the name given to transcription factors that regulate the expression of the heat shock proteins. A typical example is the heat shock factor of Drosophila melanogaster.- Function :...

 (HSF). HSPs are found in virtually all living organisms, from bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

 to human
Human
Humans are the only living species in the Homo genus...

s.

Heat-shock proteins are named according to their molecular weight. For example, Hsp60, Hsp70 and Hsp90 (the most widely-studied HSPs) refer to families of heat shock proteins on the order of 60, 70 and 90 kilodaltons
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...

 in size, respectively. The small 8 kilodalton protein ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...

, which marks proteins for degradation, also has features of a heat shock protein.

Discovery

It is known that rapid heat hardening can be elicited by a brief exposure of cells to sub-lethal high temperature, which in turn provides protection from subsequent and more severe temperature. In 1962, Ritossa reported that heat and the metabolic uncoupler dinitrophenol induced a characteristic pattern of puffing in the chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

s of Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...

. This discovery eventually led to the identification of the heat-shock proteins (HSP) or stress proteins whose expression these puffs represented. Increased synthesis of selected proteins in Drosophila cells following stresses such as heat shock was first reported in 1974.

Beginning in the mid-1980s, investigators recognized that many HSPs function as molecular chaperones and thus play a critical role in protein folding, intracellular trafficking of proteins, and coping with proteins denatured by heat and other stresses. Accordingly, the study of stress proteins has undergone explosive growth.

Upregulation in stress

Production of high levels of heat shock proteins can also be triggered by exposure to different kinds of environmental stress
Stress (biology)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...

 conditions, such as infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

, inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

, exercise, exposure of the cell to toxins (ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...

, arsenic
Arsenic
Arsenic is a chemical element with the symbol As, atomic number 33 and relative atomic mass 74.92. Arsenic occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. It was first documented by Albertus Magnus in 1250.Arsenic is a metalloid...

, trace metal
Trace metal
Trace metals are metals in extremely small quantities that reside in or are present in animal and plant cells and tissue. They are a necessary part of good nutrition, although they can be toxic if ingested in excess quantities....

s and ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...

 light, among many others), starvation
Starvation
Starvation is a severe deficiency in caloric energy, nutrient and vitamin intake. It is the most extreme form of malnutrition. In humans, prolonged starvation can cause permanent organ damage and eventually, death...

, hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

 (oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

 deprivation), nitrogen deficiency (in plants), or water deprivation. Consequently, the heat shock proteins are also referred to as stress proteins and their upregulation
Downregulation and upregulation
Downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable...

 is sometimes described more generally as part of the stress response.

The mechanism by which heat-shock (or other environmental stressors) activates the heat shock factor has been determined in bacteria. During heat stress outer membrane proteins do not fold and cannot insert correctly into the outer membrane. They accumulate in the periplasmic space. These OMP's are detected by DegS, an inner membrane protease, that passes the signal through the membrane to the sigmaE transcription factor. However, some studies suggest that an increase in damaged or abnormal proteins brings HSPs into action.

Some bacterial heat shock proteins are upregulated via a mechanism involving RNA thermometers such as the FourU thermometer
FourU thermometer
FourU thermometers are a class of non-coding RNA thermometers found in Salmonella. They are named 'FourU' due to the four highly conserved uridine nucleotides found directly opposite the Shine-Dalgarno sequence on hairpin II ....

, ROSE element
Repression of heat shock gene expression (ROSE) element
The repression of heat shock gene expression element is an RNA element found in the 5' UTR of some heat shock protein's mRNAs. The ROSE element is an RNA thermometer that negatively regulates heat shock gene expression. The secondary structure is thought to be altered by temperature, thus it is an...

 and the Hsp90 cis-regulatory element
Hsp90 cis-regulatory element
The Hsp90 cis regulatory element is an RNA element found in the 5' UTR of the Drosophila hsp90 mRNA. It is required for increased translational efficiency during the heat shock response....

.

Role as chaperone

Heat shock proteins function as intra-cellular chaperones for other proteins. They play an important role in protein-protein interactions such as folding and assisting in the establishment of proper protein conformation (shape) and prevention of unwanted protein aggregation. By helping to stabilize partially unfolded proteins, HSPs aid in transporting proteins across membranes within the cell.

Some members of the HSP family are expressed at low to moderate levels in all organisms because of their essential role in protein maintenance.

Housekeeping

Heat-shock proteins also occur under non-stressful conditions, simply "monitoring" the cell's proteins. Some examples of their role as "monitors" are that they carry old proteins to the cell's "recycling bin" (proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria.  In eukaryotes, they are located in the nucleus and the cytoplasm.  The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...

) and they help newly synthesised proteins fold properly.

These activities are part of a cell's own repair system, called the "cellular stress response" or the "heat-shock response".

Cardiovascular

Heat shock proteins appear to serve a significant cardiovascular role. Hsp90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...

, hsp84, hsp70
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...

, hsp27
Hsp27
Heat shock protein 27 also known as heat shock protein beta-1 is a protein that in humans is encoded by the HSPB1 gene.Hsp27 is a chaperone of the sHsp group among ubiquitin, α-crystallin, Hsp20 and others...

, hsp20
Hsp20
Heat shock protein Hsp20 is a family of heat shock proteins.Prokaryotic and eukaryotic organisms respond to heat shock or other environmental stress by inducing the synthesis of proteins collectively known as heat-shock proteins . Amongst them is a family of proteins with an average molecular...

, and alpha B crystallin all have been reported as having roles in the cardiovasculature.

Hsp90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...

 binds both endothelial nitric oxide synthase
Endothelial NOS
Endothelial NOS , also known as nitric oxide synthase 3 or constitutive NOS , is an enzyme that in humans is encoded by the NOS3 gene....

 and soluble guanylate cyclase
Guanylate cyclase
-Reaction:Guanylate cyclase catalyzes the reaction of guanosine triphosphate to 3',5'-cyclic guanosine monophosphate and pyrophosphate:-Types:...

 which in turn are involved in vascular relaxation.

A downstream kinase of the nitric oxide cell signalling pathway, protein kinase G, phosphorylates a small heat shock protein, hsp20. Hsp20 phosphorylation correlates well with smooth muscle relaxation and is one significant phosphoprotein involved in the process. Hsp20 appears significant in development of the smooth muscle phenotype during development. Hsp20 also serves a significant role in preventing platelet aggregation, cardiac myocyte function and prevention of apoptosis after ischemic injury, and skeletal muscle function and muscle insulin response.

Hsp27 is a major phosphoprotein during muscle contraction. Hsp27 functions in smooth muscle migration and appears to serve an integral role.

Immunity

Extracellular and membrane bound heat-shock proteins, especially Hsp70
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...

 are involved in binding antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

s and presenting them to the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

.

Clinical significance

Heat Shock Factor 1 (HSF1
HSF1
Heat shock factor protein 1 is a protein that in humans is encoded by the HSF1 gene.-Function:The product of this gene is a heat-shock transcription factor. Transcription of heat-shock genes is rapidly induced after temperature stress...

) is a transcription factor that is involved in the upregulation of Hsp70 protein expression. Recently it was discovered that HSF1 is a powerful multifaceted modifier of carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...

. HSF1 knockout mice show significantly decreased incidence of skin tumor after topical application of DMBA
7,12-Dimethylbenz(a)anthracene
7,12-Dimethylbenzanthracene is an immunosuppressor and a powerful organ-specific laboratory carcinogen. Also known as 7,12-dimethylbenz[α]anthracene or DMBA, this substance is widely used in many research laboratories studying cancer. DMBA serves as a tumor initiator by making necessary mutations...

 (7,12-dimethylbenzanthracene), a mutagen
Mutagen
In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...

.

Cancer vaccine adjuvant

Given their role in antigen presentation
Antigen presentation
Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells....

, HSPs are useful as immunologic adjuvant
Immunologic adjuvant
In immunology, an adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect in itself. The word “adjuvant” comes from the Latin word adiuvare, meaning to help or aid...

s in boosting the response to a vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

. Furthermore, some researchers speculate that HSPs may be involved in binding protein fragments from dead malignant cells and presenting them to the immune system. Therefore HSPs may be useful for increasing the effectiveness of cancer vaccines.

Anticancer therapeutics

Intracellular heat shock proteins are highly expressed in cancerous cells and are essential to the survival of these cell types. Hence small molecule
Small molecule
In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...

 inhibitors of HSPs, especially Hsp90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...

 show promise as anticancer agents. The potent Hsp90 inhibitor 17-AAG
17-N-allylamino-17-demethoxygeldanamycin
17-N-Allylamino-17-demethoxygeldanamycin is a derivative of the antibiotic geldanamycin that is being studied in the treatment of cancer, specific young patients with certain types of leukemia or solid tumors, especially kidney tumors....

 is currently in clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s for the treatment of several types of cancer.

Agricultural

Researchers are also investigating the role of HSPs in conferring stress tolerance to hybridized plants, hoping to address drought and poor soil conditions for farming.

Classification

The principal heat-shock proteins that have chaperone activity belong to five conserved classes: HSP33
HSP33
Hsp33 protein is a molecular chaperone, distinguished from all other known chaperones by its mode of functional regulation. Its activity is redox regulated. Hsp33 is a cytoplasmically localized protein with highly reactive cysteines that respond quickly to changes in the redox environment...

, HSP60
HSP60
Heat shock proteins are generally responsible for preventing damage to proteins in response to high levels of heat. Heat shock proteins are classified into six major families based on their molecular mass: small HSPs, HSP40, HSP60, HSP70, HSP90, and HSP110...

, HSP70
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...

, HSP90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...

, HSP100, and the small heat-shock proteins (sHSPs).
Approximate molecular weight
Molecular mass
The molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u...


(kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...

)
Prokaryotic
Prokaryote
The prokaryotes are a group of organisms that lack a cell nucleus , or any other membrane-bound organelles. The organisms that have a cell nucleus are called eukaryotes. Most prokaryotes are unicellular, but a few such as myxobacteria have multicellular stages in their life cycles...

 proteins
Eukaryotic
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...

 proteins
Function
10 kDa
GroES
Heat shock 10 kDa protein 1 also known as chaperonin 10 or early-pregnancy factor is a protein that in humans is encoded by the HSPE1 gene. The homolog in E...

GroES Hsp10
20-30 kDa GrpE The HspB group of Hsp. Eleven members in mammals including Hsp27
Hsp27
Heat shock protein 27 also known as heat shock protein beta-1 is a protein that in humans is encoded by the HSPB1 gene.Hsp27 is a chaperone of the sHsp group among ubiquitin, α-crystallin, Hsp20 and others...

, HSPB6
HSPB6
Heat shock protein beta-6 is a protein that in humans is encoded by the HSPB6 gene.HSPB6 also known as hsp20 is a 17-kDa member of the small heat shock family of proteins...

 or HspB1
40 kDa DnaJ Hsp40 Co-factor of Hsp70
60 kDa
GroEL
GroEL belongs to the chaperonin family of molecular chaperones, and is found in a large number of bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex GroES...

GroEL, 60kDa antigen Hsp60 Involved in protein folding after its post-translational import to the mitochondrion/chloroplast
70 kDa
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...

DnaK The HspA group of Hsp including Hsp71, Hsp70
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...

, Hsp72
HSPA1A
Heat shock 70 kDa protein 1 is a protein that in humans is encoded by the HSPA1A gene.-Interactions:HSPA1A has been shown to interact with ASK1, STUB1, MSR1, BAG3, Parkin , Fanconi anemia, complementation group C, GPR37, HSF1 and AIFM1....

, Grp78 (BiP), Hsx70 found only in primates
Protein folding and unfolding, provides thermotolerance to cell on exposure to heat stress. Also prevents protein folding during post-translational import into the mitochondria/chloroplast.
90 kDa
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...

HtpG, C62.5 The HspC group of Hsp including Hsp90, Grp94 Maintenance of steroid receptors and transcription factors
100 kDa ClpB, ClpA, ClpX Hsp104, Hsp110 Tolerance of extreme temperature


Although the most important members of each family are tabulated here, it should be noted that some species may express additional chaperones, co-chaperone
Co-chaperone
Co-chaperones are proteins that assist chaperones in protein folding and other functions.-List of Co-chaperones:*Aha1*auxilin*BAG1*CAIR-1/Bag-3*CDC37/p50*Chp1*Cysteine string protein *Cyp40*Djp1*DnaJ*E3/E4-ubiquitin ligase*FKBP52*GAK*GroES...

s, and heat shock proteins not listed. Additionally, many of these proteins may have multiple splice variants
Splicing (genetics)
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...

 (Hsp90α and Hsp90β, for instance) or conflicts of nomenclature (Hsp72 is sometimes called Hsp70).

See also

  • Chaperone
  • Chaperonin
    Chaperonin
    Chaperonins are proteins that fold and unfold other proteins. Newly made proteins usually must fold from a linear chain of amino acids into a three-dimensional form. Chaperonins belong to a large class of molecules that assist protein folding, called molecular chaperones...

  • Co-chaperone
    Co-chaperone
    Co-chaperones are proteins that assist chaperones in protein folding and other functions.-List of Co-chaperones:*Aha1*auxilin*BAG1*CAIR-1/Bag-3*CDC37/p50*Chp1*Cysteine string protein *Cyp40*Djp1*DnaJ*E3/E4-ubiquitin ligase*FKBP52*GAK*GroES...

  • FourU thermometer
    FourU thermometer
    FourU thermometers are a class of non-coding RNA thermometers found in Salmonella. They are named 'FourU' due to the four highly conserved uridine nucleotides found directly opposite the Shine-Dalgarno sequence on hairpin II ....

  • Hsp90 cis-regulatory element
    Hsp90 cis-regulatory element
    The Hsp90 cis regulatory element is an RNA element found in the 5' UTR of the Drosophila hsp90 mRNA. It is required for increased translational efficiency during the heat shock response....

  • ROSE element
    Repression of heat shock gene expression (ROSE) element
    The repression of heat shock gene expression element is an RNA element found in the 5' UTR of some heat shock protein's mRNAs. The ROSE element is an RNA thermometer that negatively regulates heat shock gene expression. The secondary structure is thought to be altered by temperature, thus it is an...

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