Chaperone
Encyclopedia
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
, molecular chaperones are 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 that assist the non-covalent folding or unfolding and the assembly or disassembly of other macromolecular structures, but do not occur in these structures when the structures are performing their normal biological functions having completed the processes of folding and/or assembly. The common perception that chaperones are concerned primarily with protein folding is incorrect. The first protein to be called a chaperone assists the assembly of nucleosome
Nucleosome
Nucleosomes are the basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound around a histone protein core. This structure is often compared to thread wrapped around a spool....
s from folded histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
s and DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and such assembly chaperones, especially in the nucleus, are concerned with the assembly of folded subunits into oligomeric structures.
Molecular chaperones do not necessarily convey steric information required for proteins to fold: Thus, statements of the form 'chaperones fold proteins' can be misleading. One major function of chaperones is to prevent both newly synthesised polypeptide chains and assembled subunits from aggregating into nonfunctional structures. It is for this reason that many chaperones, but by no means all, are also heat shock protein
Heat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
s because the tendency to aggregate increases as proteins are denatured by stress. However, 'steric chaperones' directly assist in the folding of specific proteins by providing essential steric information, e.g. prodomains of bacterial proteases, lipase-specific foldases, or chaperones in fimbrial adhesion systems.
Location and functions
Many chaperones are heat shock proteinHeat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
s, that is, proteins expressed
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
in response to elevated temperatures or other cellular stresses. The reason for this behaviour is that protein folding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
is severely affected by heat and, therefore, some chaperones act to repair the potential damage caused by misfolding. Other chaperones are involved in folding newly made proteins as they are extruded from the ribosome. Although most newly synthesized proteins can fold in absence of chaperones, a minority strictly requires them for the same.
Macromolecular crowding
Macromolecular crowding
The phenomenon of macromolecular crowding alters the properties of molecules in a solution when high concentrations of macromolecules such as proteins are present. Such conditions occur routinely in living cells; for instance, the cytosol of Escherichia coli contains about 300–400 milligrammes per...
may be important in chaperone function. The crowded environment of the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
can accelerate the folding process, since a compact folded protein will occupy less volume than an unfolded protein chain. However, crowding can reduce the yield of correctly-folded protein by increasing protein aggregation
Protein aggregation
Protein aggregation is the aggregation of mis-folded proteins, and is thought to be responsible for many degenerative diseases, such as Alzheimer's. It has also been implicated in CAG repeat diseases....
. Crowding may also increase the effectiveness of the chaperone proteins such as GroEL
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...
, which could counteract this reduction in folding efficiency.
More information on the various types and mechanisms of a subset of chaperones that encapsulate their folding substrates can be found in the article for 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...
s. Chaperonins are characterized by a stacked double-ring structure and are found in prokaryotes, in the cytosol of eukaryotes, and in mitochondria.
Other types of chaperones are involved in transport across membranes
Biological membrane
A biological membrane or biomembrane is an enclosing or separatingmembrane that acts as a selective barrier, within or around a cell. It consists of a lipid bilayer with embedded proteins that may constitute close to 50% of membrane content...
, for example membranes of the mitochondria and endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER) in eukaryote
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...
s. Bacterial translocation—specific chaperone maintains newly synthesized precursor
Protein precursor
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein that can be turned into an active form by posttranslational modification. The name of the precursor for a protein is often prefixed by pro...
polypeptide chains in a translocation
Protein targeting
Protein targeting or protein sorting is the mechanism by which a cell transports proteins to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle, any of several interior membranes, the cell's outer membrane, or its exterior via secretion...
-competent (generally unfolded) state and guides them to the translocon
Translocon
The translocon is the complex of proteins associated with the translocation of nascent polypeptides across membranes. In eukaryotes the polypeptides are transported into the interior space of the endoplasmic reticulum from the cytosol...
.
New functions for chaperones continue to be discovered, such as assistance in protein degradation, bacterial adhesin activity, and in responding to diseases linked to protein aggregation (e.g. see prion
Prion
A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...
).
Human chaperone proteins
Chaperones are found in, for example, the endoplasmic reticulum (ER), since protein synthesis often occurs in this area.Endoplasmic reticulum
In the endoplasmic reticulum (ER) there are general, lectin- and non-classical molecular chaperones helping to fold proteins.- General chaperones: BiPBIPBip or BIP may refer to:* Basic Imaging Profile, Bluetooth profile which is designed for sending images between devices and includes the ability to resize, and convert images to make them suitable for the receiving device....
, GRP94, GRP170. - Lectin chaperones: calnexinCalnexinCalnexin is a 90kDa integral protein of the endoplasmic reticulum . It consists of a large N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short , acidic cytoplasmic tail....
and calreticulinCalreticulinCalreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 is a protein that in humans is encoded by the CALR gene.... - Non-classical molecular chaperones: HSP47 and ERp29ERP29Endoplasmic reticulum protein 29 is a human chaperone protein. ERP29 is the human gene encoding it.-Gene:-Further reading:...
- Folding chaperones:
- Protein disulfide isomeraseProtein disulfide isomeraseProtein disulfide isomerase or PDI is an enzyme in the endoplasmic reticulum in eukaryotes that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold...
(PDI), - Peptidyl prolyl cis-trans-isomerase (PPI),
- ERp57
- Protein disulfide isomerase
Nomenclature and examples of bacterial and archeal chaperones
There are many different families of chaperones; each family acts to aid protein folding in a different way. In bacteria like E. coli, many of these proteins are highly expressed under conditions of high stress, for example, when placed in high temperatures. For this reason, the term "heat shock proteinHeat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
" has historically been used to name these chaperones. The prefix "Hsp" designates that the protein is a heat shock protein.
Hsp60
Hsp60 (GroEL/GroES complex in E. coli) is the best characterized large (~ 1 MDa) chaperone complex. GroELGroEL
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...
is a double-ring 14mer with a greasy hydrophobic patch at its opening; it is so large it can accommodate native folding of 54-kDa GFP
Green fluorescent protein
The green fluorescent protein is a protein composed of 238 amino acid residues that exhibits bright green fluorescence when exposed to blue light. Although many other marine organisms have similar green fluorescent proteins, GFP traditionally refers to the protein first isolated from the...
in its lumen. GroES
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...
is a single-ring heptamer that binds to GroEL in the presence of ATP or ADP. GroEL/GroES may not be able to undo previous aggregation, but it does compete in the pathway of misfolding and aggregation. Also acts in mitochondrial matrix
Matrix (biology)
In biology, matrix is the material between animal or plant cells, in which more specialized structures are embedded, and a specific part of the mitochondrion that is the site of oxidation of organic molecules. The internal structure of connective tissues is an extracellular matrix...
as molecular chaperone.
Hsp70
Hsp70 (DnaK in E. coli) is perhaps the best characterized small (~ 70 kDa) chaperone.The 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...
proteins are aided by Hsp40 proteins (DnaJ in E. coli), which increase the ATP consumption rate and activity of the Hsp70s.
It has been noted that increased expression of Hsp70 proteins in the cell results in a decreased tendency toward apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Although a precise mechanistic understanding has yet to be determined, it is known that Hsp70s have a high-affinity bound state to unfolded proteins when bound to ADP
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
, and a low-affinity state when bound to ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
.
It is thought that many Hsp70s crowd around an unfolded substrate, stabilizing it and preventing aggregation until the unfolded molecule folds properly, at which time the Hsp70s lose affinity for the molecule and diffuse away. Hsp70 also acts as a mitochondrial and chloroplastic molecular chaperone in eukaryotes.
Hsp90
Hsp90 (HtpG in E. coli) may be the least understood chaperone. Its molecular weight is about 90 kDa, and it is necessary for viability in eukaryotes (possibly for prokaryotes as well).Heat shock protein 90 (Hsp90) is a molecular chaperone essential for activating many signaling proteins in the eukaryotic cell.
Each 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...
has an ATP-binding domain, a middle domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
, and a dimerization
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
domain. Originally thought to clamp onto their substrate protein (also known as a client protein) upon binding ATP, the recently published structures by Vaughan et al. and Ali et al. indicate that client proteins may bind externally to both the N-terminal and middle domains of Hsp90.
Hsp90 may also require 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-like immunophilins, Sti1, p50 (Cdc37
CDC37
Hsp90 co-chaperone Cdc37 is a protein that in humans is encoded by the CDC37 gene.The protein encoded by this gene is highly similar to Cdc 37, a cell division cycle control protein of Saccharomyces cerevisiae. This protein is a molecular chaperone with specific function in cell signal transduction...
), and Aha1, and also cooperates with the Hsp70 chaperone system.
Hsp100
Hsp100 (Clp family in E. coli) proteins have been studied in vivoIn vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
and in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
for their ability to target and unfold tagged and misfolded proteins.
Proteins in the Hsp100/Clp family form large hexameric structures with unfoldase activity in the presence of ATP. These proteins are thought to function as chaperones by processively threading client proteins through a small 20 Å (2 nm) pore, thereby giving each client protein a second chance to fold.
Some of these Hsp100 chaperones, like ClpA and ClpX, associate with the double-ringed tetradecameric serine protease
Serine protease
Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...
ClpP; instead of catalyzing the refolding of client proteins, these complexes are responsible for the targeted destruction of tagged and misfolded proteins.
Hsp104, the Hsp100 of Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
, is essential for the propagation of many yeast prions. Deletion of the HSP104 gene results in cells that are unable to propagate certain prions.
History
The investigation of chaperones has a long history. The term `molecular chaperone` appeared first in the literature in 1978, and was invented by Ron Laskey to describe the ability of a nuclear protein called nucleoplasmin to prevent the aggregation of folded histone proteins with DNA during the assembly of nucleosomes. The term was later extended by R. John EllisR. John Ellis
Reginald John Ellis, FRS, is a British scientist at The University of Warwick. Ellis was born on 12th February, 1935, and educated at Highbury Grammar School, London. He studied at King's College, London and obtained a BSc degree in 1956 and PhD in 1960, for thesis research on the enzymology of...
in 1987 to describe proteins that mediated the post-translational assembly of protein complexes. In 1988, it was realised that similar proteins mediated this process in both prokaryotes and eukaryotes. The details of this process were determined in 1989, when the ATP-dependent protein folding was demonstrated in vitro.
See also
- ChaperoninChaperoninChaperonins 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-chaperoneCo-chaperoneCo-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...
- Heat shock proteinHeat shock proteinHeat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
- Pharmacoperone
- ProteasomeProteasomeProteasomes 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...