Chaperone Protein
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molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and phys ...
, molecular chaperones are
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
s that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assist large proteins in proper
protein folding Protein folding is the physical process by which a protein chain is translated to its native three-dimensional structure, typically a "folded" conformation by which the protein becomes biologically functional. Via an expeditious and reprodu ...
during or after synthesis, and after partial denaturation. Chaperones are also involved in the translocation of proteins for
proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
. The first molecular chaperones discovered were a type of assembly chaperones which assist in the assembly of
nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamen ...
s from folded
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn ar ...
s and DNA. One major function of molecular chaperones is to prevent the aggregation of misfolded proteins, thus many chaperone proteins are classified as
heat shock protein Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exp ...
s, as the tendency for protein aggregation is increased by heat stress. The majority of molecular chaperones do not convey any
steric Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
information for protein folding, and instead assist in protein folding by binding to and stabilizing folding intermediates until the polypeptide chain is fully translated. The specific mode of function of chaperones differs based on their target proteins and location. Various approaches have been applied to study the structure, dynamics and functioning of chaperones. Bulk biochemical measurements have informed us on the protein folding efficiency, and prevention of aggregation when chaperones are present during protein folding. Recent advances in single-molecule analysis have brought insights into structural heterogeneity of chaperones, folding intermediates and affinity of chaperones for unstructured and structured protein chains.


Functions of molecular chaperones

Many chaperones are
heat shock protein Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exp ...
s, that is, proteins expressed in response to elevated temperatures or other cellular stresses. Heat shock protein chaperones are classified based on their observed molecular weights into Hsp60, Hsp70, Hsp90, Hsp104, and small Hsps. The Hsp60 family of protein chaperones are termed chaperonins, and are characterized by a stacked double-ring structure and are found in prokaryotes, in the cytosol of eukaryotes, and in mitochondria. Some chaperone systems work as foldases: they support the folding of proteins in an ATP-dependent manner (for example, the
GroEL GroEL is a protein which belongs to the chaperonin family of molecular chaperones, and is found in many bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein c ...
/ GroES or the
DnaK The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an importa ...
/ DnaJ/ GrpE system). Although most newly synthesized proteins can fold in absence of chaperones, a minority strictly requires them for the same. Other chaperones work as holdases: they bind folding intermediates to prevent their aggregation, for example DnaJ or Hsp33. Chaperones can also work as disaggregases, which interact with aberrant protein assemblies and revert them to monomers. Some chaperones can assist in
protein degradation Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases ...
, leading proteins to
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the form ...
systems, such as the ubiquitin-proteasome system in
eukaryotes Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
. Chaperone proteins participate in the folding of over half of all mammalian proteins. Macromolecular crowding may be important in chaperone function. The crowded environment of the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
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 In molecular biology, protein aggregation is a phenomenon in which intrinsically-disordered or mis-folded proteins aggregate (i.e., accumulate and clump together) either intra- or extracellularly. Protein aggregates have been implicated in a wi ...
. Crowding may also increase the effectiveness of the chaperone proteins such as
GroEL GroEL is a protein which belongs to the chaperonin family of molecular chaperones, and is found in many bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein c ...
, which could counteract this reduction in folding efficiency. Some highly specific 'steric chaperones' convey unique structural information onto proteins, which cannot be folded spontaneously. Such proteins violate Anfinsen's dogma, requiring
protein dynamics Proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these stat ...
to fold correctly. Other types of chaperones are involved in transport across membranes, for example membranes of the mitochondria and
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
(ER) in
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
s. A
bacterial Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
translocation-specific chaperone SecB maintains newly synthesized precursor
polypeptide chain Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides ...
s in a
translocation Translocation may refer to: * Chromosomal translocation, a chromosome abnormality caused by rearrangement of parts ** Robertsonian translocation, a chromosomal rearrangement in pairs 13, 14, 15, 21, and 22 ** Nonreciprocal translocation, transfer ...
-competent ( generally unfolded) state and guides them to the
translocon The translocon (also known as a translocator or translocation channel) is a complex of proteins associated with the translocation of polypeptides across membranes. In eukaryotes the term translocon most commonly refers to the complex that transport ...
. New functions for chaperones continue to be discovered, such as bacterial adhesin activity, induction of aggregation towards non-amyloid aggregates, suppression of toxic protein oligomers via their clustering, and in responding to diseases linked to protein aggregation and cancer maintenance.


Human chaperone proteins

In human cell lines, chaperone proteins were found to compose ~10% of the gross proteome mass, and are ubiquitously and highly expressed across human tissues. Chaperones are found extensively in the endoplasmic reticulum (ER), since
protein synthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...
often occurs in this area.


Endoplasmic reticulum

In the endoplasmic reticulum (ER) there are general, lectin- and non-classical molecular chaperones that moderate protein folding. *General chaperones: GRP78/BiP,
GRP94 Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the ''HSP90B1'' gene. HSP90B1 is an HSP90 paralogue that is found in the endoplasmic reticulum ...
, GRP170. *Lectin chaperones:
calnexin Calnexin (CNX) is 67kDa integral protein (that appears variously as a 90kDa, 80kDa, or 75kDa band on western blotting depending on the source of the antibody) of the endoplasmic reticulum (ER). It consists of a large (50 kDa) N-terminal calcium- ...
and calreticulin *Non-classical molecular chaperones: HSP47 and ERp29 *Folding chaperones: ** Protein disulfide isomerase (PDI), **''Peptidyl prolyl cis-trans isomerase'' (PPI),
Prolyl isomerase Prolyl isomerase (also known as peptidylprolyl isomerase or PPIase) is an enzyme () found in both prokaryotes and eukaryotes that interconverts the ''cis'' and ''trans'' isomers of peptide bonds with the amino acid proline. Proline has an unusu ...
**
ERp57 Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) ...


Nomenclature and examples of chaperone families

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 the bacterium is placed in high temperatures, thus heat shock protein chaperones are the most extensive. A variety of nomenclatures are in use for chaperones. As heat shock proteins, the names are classically formed by "Hsp" followed by the approximate molecular mass in kilodaltons; such names are commonly used for eukaryotes such as yeast. The bacterial names have more varied forms, and refer directly to their appearant function at discovery. For example, "GroEL" originally stands for "phage growth defect, overcome by mutation in phage gene E, large subunit".


Hsp10 and Hsp60

Hsp10/60 (GroEL/GroES complex in ''E. coli'') is the best characterized large (~ 1 MDa) chaperone complex.
GroEL GroEL is a protein which belongs to the chaperonin family of molecular chaperones, and is found in many bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein c ...
(Hsp60) is a double-ring 14mer with a
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...
patch at its opening; it is so large it can accommodate native folding of 54-kDa GFP in its lumen. GroES (Hsp10) 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 In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ri ...
as molecular chaperone.


Hsp70 and Hsp40

Hsp70 (DnaK in ''E. coli'') is perhaps the best characterized small (~ 70 kDa) chaperone. The
Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an importa ...
proteins are aided by Hsp40 proteins (DnaJ in ''E. coli''), which increase the ATP consumption rate and activity of the Hsp70s. The two protein are named "Dna" in bacteria because they were initially identified as being required for ''E. coli'' DNA replication. It has been noted that increased expression of Hsp70 proteins in the cell results in a decreased tendency toward apoptosis. 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 Adp or ADP may refer to: Aviation * Aéroports de Paris, airport authority for the Parisian region in France * Aeropuertos del Perú, airport operator for airports in northern Peru * SLAF Anuradhapura, an airport in Sri Lanka * Ampara Air ...
, and a low-affinity state when bound to
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
. 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 has an ATP-binding domain, a middle
domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined ** Domain of definition of a partial function **Natural domain of a partial function **Domain of holomorphy of a function *Do ...
, and a
dimerization A dimer () (''wikt:di-, di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, Covalent bond, covalent or Intermolecular force, intermolecular. Dimers also have significant im ...
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-chaperones-like immunophilins, Sti1, p50 ( Cdc37), and
Aha1 Activator of 90 kDa heat shock protein ATPase homolog 1 is an enzyme that in humans is encoded by the ''AHSA1'' gene. Interactions AHSA1 has been shown to interact Advocates for Informed Choice, dba interACT or interACT Advocates for Int ...
, and also cooperates with the Hsp70 chaperone system.


Hsp100

Hsp100 (Clp family in ''E. coli'') proteins have been studied ''
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' and ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...
'' 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 proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. S ...
ClpP; instead of catalyzing the refolding of client proteins, these complexes are responsible for the targeted destruction of tagged and misfolded proteins.
Hsp104 Hsp104 is a heat-shock protein Heat shock proteins (HSP) are a family of proteins produced by cell (biology), cells in response to exposure to Stress (biology), stressful conditions. They were first described in relation to heat shock#Heat shock, h ...
, the Hsp100 of
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
, is essential for the propagation of many yeast prions. Deletion of the HSP104 gene results in cells that are unable to propagate certain
prions Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It ...
.


Bacteriophage

The
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s of bacteriophage (phage) T4 that encode
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
s with a role in determining phage T4 structure were identified using conditional lethal
mutant In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
s. Most of these proteins proved to be either major or minor structural components of the completed phage particle. However among the gene products (gps) necessary for phage assembly, Snustad identified a group of gps that act catalytically rather than being incorporated themselves into the phage structure. These gps were gp26, gp31, gp38, gp51, gp28, and gp4
ene 4 is synonymous with genes 50 and 65, and thus the gp can be designated gp4(50)(65) Ene or ENE may refer to: Ene * Ene (name), a given name and surname * Ene, a type of hydrocarbon involved in the Ene reaction and the Thiol-ene reaction * -ene'', a suffix used in the names of certain organic compounds ( alkenes) * Ene, Spani ...
The first four of these six gene products have since been recognized as being chaperone proteins. Additionally, gp40, gp57A, gp63 and gpwac have also now been identified as chaperones. Phage T4
morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...
is divided into three independent pathways: the head, the tail and the long tail fiber pathways as detailed by Yap and Rossman.Yap ML, Rossmann MG. Structure and function of bacteriophage T4. Future Microbiol. 2014;9(12):1319-1327. doi:10.2217/fmb.14.91 With regard to head morphogenesis, chaperone gp31 interacts with the bacterial host chaperone
GroEL GroEL is a protein which belongs to the chaperonin family of molecular chaperones, and is found in many bacteria. It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein c ...
to promote proper folding of the major head
capsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may ...
protein gp23.Marusich EI, Kurochkina LP, Mesyanzhinov VV. Chaperones in bacteriophage T4 assembly. Biochemistry (Mosc). 1998;63(4):399-406 Chaperone gp40 participates in the assembly of gp20, thus aiding in the formation of the connector complex that initiates head procapsid assembly. Gp4(50)(65), although not specifically listed as a chaperone, acts catalytically as a nuclease that appears to be essential for morphogenesis by cleaving packaged DNA to enable the joining of heads to tails. During overall tail assembly, chaperone proteins gp26 and gp51 are necessary for baseplate hub assembly.Leiman PG, Arisaka F, van Raaij MJ, et al. Morphogenesis of the T4 tail and tail fibers. Virol J. 2010;7:355. Published 2010 Dec 3. doi:10.1186/1743-422X-7-355 Gp57A is required for correct folding of gp12, a structural component of the baseplate short tail fibers. Synthesis of the long tail fibers depends on the chaperone protein gp57A that is needed for the trimerization of gp34 and gp37, the major structural proteins of the tail fibers. The chaperone protein gp38 is also required for the proper folding of gp37. Chaperone proteins gp63 and gpwac are employed in attachment of the long tail fibers to the tail baseplate.


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 Ellis Reginald John Ellis (born 12 February 1935) is a British scientist. Early life and education Ellis was 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 the ...
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''.


Clinical significance

There are many disorders associated with mutations in genes encoding chaperones (i.e.
multisystem proteinopathy Multisystem proteinopathy (MSP) is a dominantly inherited, pleiotropic, degenerative disorder of humans that can affect muscle, bone, and/or the central nervous system. MSP can manifest clinically as classical amyotrophic lateral sclerosis (ALS), ...
) that can affect muscle, bone and/or the central nervous system.


See also

* Biological machines * Chaperome * Chaperonin * Chemical chaperones *
Heat shock protein Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exp ...
* Heat shock factor 1 *
Molecular chaperone therapy A pharmacological chaperone or pharmacoperone is a drug that acts as a chaperone (protein), protein chaperone. That is, it contains small molecules that enter cells and serve as a molecular scaffolding in order to cause otherwise-protein folding, ...
*
Pharmacoperone A pharmacological chaperone or pharmacoperone is a drug that acts as a protein chaperone. That is, it contains small molecules that enter cells and serve as a molecular scaffolding in order to cause otherwise- misfolded mutant proteins to fold an ...
*
Proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by whi ...
*
Protein dynamics Proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these stat ...


Notes


References

{{Chaperones Protein biosynthesis