HSP60, also known as chaperonins (Cpn), is a family of
heat shock proteins originally sorted by their 60kDa molecular mass. They prevent misfolding of proteins during stressful situations such as high heat, by assisting protein folding. HSP60 belong to a large class of molecules that assist protein folding, called
molecular chaperones.
Newly made proteins usually must
fold from a linear chain of amino acids into a three-dimensional
tertiary structure
Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may in ...
. The energy to fold proteins is supplied by non-covalent interactions between the amino acid side chains of each protein, and by solvent effects. Most proteins spontaneously fold into their most stable three-dimensional conformation, which is usually also their functional conformation, but occasionally proteins mis-fold. Molecular chaperones catalyze protein refolding by accelerating partial unfolding of misfolded proteins, aided by energy supplied by the hydrolysis of
adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known form ...
(ATP). Chaperonin proteins may also tag misfolded proteins to be degraded.
Structure
The structure of these chaperonins resemble two donuts stacked on top of one another to create a barrel. Each ring is composed of either 7, 8 or 9 subunits depending on the organism in which the chaperonin is found. Each ~60kDa peptide chain can be divided into three domains, apical, intermediate, and equatorial.
The original chaperonin is proposed to have evolved from a
peroxiredoxin
Peroxiredoxins (Prxs, ; HGNC root symbol ''PRDX'') are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels and thereby mediate signal transduction in mammalian cells. The family members in humans are ...
.
Classification
Group I
Group I chaperonins (Cpn60) are found in
bacteria
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 am ...
as well as
organelles
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
of
endosymbiotic origin:
chloroplasts
A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it in t ...
and
mitochondria
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is u ...
.
The GroEL/GroES complex in ''
E. coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Es ...
'' is a Group I chaperonin and the best characterized large (~ 1 MDa) chaperonin complex.
*
GroEL is a double-ring 14mer with a greasy
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 and can accommodate the native folding of substrates 15-60 kDa in size.
*
GroES (is a single-ring heptamer that binds to GroEL in the presence of ATP or transition state analogues of ATP hydrolysis, such as ADP-AlF
3. It is like a cover that covers GroEL (box/bottle).
GroEL/GroES may not be able to undo protein aggregates, but kinetically it competes in the pathway of misfolding and aggregation, thereby preventing aggregate formation.
The Cpn60 subfamily was discovered in 1998.
It was sequenced in 1992. The cpn10 and cpn60 oligomers also require Mg
2+-ATP in order to interact to form a functional complex.
The binding of cpn10 to cpn60 inhibits the weak
ATPase
ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
activity of cpn60.
The
RuBisCO
Ribulose-1,5-bisphosphate carboxylase-oxygenase, commonly known by the abbreviations RuBisCo, rubisco, RuBPCase, or RuBPco, is an enzyme () involved in the first major step of carbon fixation, a process by which atmospheric carbon dioxide is con ...
subunit binding protein is a member of this family.
The crystal structure of ''
Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...
'' GroEL has been resolved to 2.8 Å.
Some bacteria use multiple copies of this chaperonin, probably for different peptides.
Group II
Group II chaperonins (TCP-1), found in the
eukaryotic
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 ...
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 mitochond ...
and in
archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archae ...
, are more poorly characterized.
* The complex in archaea is called the
thermosome
A thermosome is a group II chaperonin protein complex that functions in archaea. It is the homolog of eukaryotic CCT. This group II chaperonin is an ATP-dependent chaperonin that is responsible for folding or refolding of incipient or denatured ...
. A homo-16mer in some archaea, it is regarded as the prototypical type II chaperonin.
*
TRiC, the eukaryotic chaperonin, is composed of two rings of eight different though
related subunits, each thought to be represented once per eight-membered ring. TRiC was originally thought to fold only the cytoskeletal proteins actin and tubulin but is now known to fold dozens of substrates.
''
Methanococcus maripaludis
''Methanococcus maripaludis'' is a species of methanogen. It is anaerobic, weakly motile, non-spore
In biology, a spore is a unit of sexual or asexual reproduction that may be adapted for dispersal and for survival, often for extended p ...
'' chaperonin (Mm cpn) is composed of sixteen identical subunits (eight per ring). It has been shown to fold the mitochondrial protein rhodanese; however, no natural substrates have yet been identified.
Group II chaperonins are not thought to utilize a GroES-type cofactor to fold their substrates. They instead contain a "built-in" lid that closes in an ATP-dependent manner to encapsulate its substrates, a process that is required for optimal protein folding activity. They also interact with a co-chaperone,
prefoldin
Prefoldin (GimC) is a superfamily of proteins used in protein folding complexes. It is classified as a heterohexameric molecular chaperone in both archaea and eukarya, including humans. A prefoldin molecule works as a transfer protein in conju ...
, that helps move the substrate in.
Other families
Group III includes some bacterial Cpns that are related to Group II. They have a lid, but the lid opening is noncooperative in them. They are thought to be an ancient relative of Group II.
A Group I chaperonin gp146 from
phage EL
A bacteriophage (), also known informally as a ''phage'' (), is a duplodnaviria virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek φαγεῖν ('), meaning "to devour". Bacter ...
does not use a lid, and its donut interface is more similar to Group II. It might represent another ancient type of chaperonin.
Mechanism of action
Chaperonins undergo large conformational changes during a folding reaction as a function of the enzymatic
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolys ...
of ATP as well as binding of substrate proteins and cochaperonins, such as GroES. These conformational changes allow the chaperonin to bind an unfolded or misfolded protein, encapsulate that protein within one of the cavities formed by the two rings, and release the protein back into solution. Upon release, the substrate protein will either be folded or will require further rounds of folding, in which case it can again be bound by a chaperonin.
The exact mechanism by which chaperonins facilitate folding of substrate proteins is unknown. According to recent analyses by different experimental techniques, GroEL-bound substrate proteins populate an ensemble of compact and locally expanded states that lack stable tertiary interactions.
A number of models of chaperonin action have been proposed, which generally focus on two (not mutually exclusive) roles of chaperonin interior: passive and active. Passive models treat the chaperonin cage as an inert form, exerting influence by reducing the conformational space accessible to a protein substrate or preventing intermolecular interactions e.g. by aggregation prevention.
The active chaperonin role is in turn involved with specific chaperonin–substrate interactions that may be coupled to conformational rearrangements of the chaperonin.
Probably the most popular model of the chaperonin active role is the iterative annealing mechanism (IAM), which focuses on the effect of iterative, and hydrophobic in nature, binding of the protein substrate to the chaperonin. According to computational simulation studies, the IAM leads to more productive folding by unfolding the substrate from misfolded conformations
or by prevention from protein misfolding through changing the folding pathway.
Conservation of structural and functional homology
As mentioned, all cells contain chaperonins.
* In bacteria, the archetype is the well-characterized chaperonin
GroEL from ''
E. coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Es ...
''.
* In
archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archae ...
, the chaperonin is called the
thermosome
A thermosome is a group II chaperonin protein complex that functions in archaea. It is the homolog of eukaryotic CCT. This group II chaperonin is an ATP-dependent chaperonin that is responsible for folding or refolding of incipient or denatured ...
.
* In
eukarya
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. Bacte ...
, the cytoplasmic chaperonin is called CCT (also called
TRiC).
These protein complexes appear to be essential for life in ''E. coli'', ''
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 be ...
'' and higher eukaryotes. While there are differences between eukaryotic, bacterial and archaeal chaperonins, the general structure and mechanism are conserved.
Bacteriophage T4 morphogenesis
The gene product 31 (gp31) of
bacteriophage T4 is a protein required for bacteriophage morphogenesis that acts
catalytically rather than being incorporated into the bacteriophage structure.
The bacterium ''E. coli'' is the host for bacteriophage T4. The bacteriophage encoded gp31 protein appears to be homologous to the ''E. coli'' cochaperonin protein
GroES and is able to substitute for it in the assembly of phage T4 virions during infection.
Like GroES, gp31 forms a stable complex with
GroEL chaperonin that is absolutely necessary for the folding and assembly ''in vivo'' of the bacteriophage T4 major capsid protein gp23.
[
The main reason for the phage to need its own GroES homolog is that the gp23 protein is too large to fit into a conventional GroES cage. gp31 has longer loops that create a taller container.]
Clinical significance
Human GroEL is the immunodominant antigen of patients with Legionnaire's disease, and is thought to play a role in the protection of the Legionella bacteria from oxygen radical
Radical may refer to:
Politics and ideology Politics
* Radical politics, the political intent of fundamental societal change
*Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe an ...
s within macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s. This hypothesis is based on the finding that the cpn60 gene is upregulated in response to hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3 ...
, a source of oxygen radicals. Cpn60 has also been found to display strong antigenicity in many bacterial species and has the potential for inducing immune protection against unrelated bacterial infections.
Examples
Human genes encoding proteins containing this domain include:
* BBS10
Bardet–Biedl syndrome 10, also known as BBS10 is a human gene.
Function
The Bardet-Biedl syndrome 10 protein has distant sequence homology to type II chaperonins. As a molecular chaperone, this protein may affect the folding or stability of ...
* CCT1; CCT2; CCT3; CCT4; CCT5; CCT6A; CCT6B
T-complex protein 1 subunit zeta-2 is a protein that in humans is encoded by the ''CCT6B'' gene.
This gene encodes a molecular chaperone that is a member of the TRiC complex. This complex consists of two identical stacked rings, each containin ...
; CCT7; CCT8
T-complex protein 1 subunit theta is a protein that in humans is encoded by the ''CCT8'' gene. The CCT8 protein is a component of the TRiC complex.
See also
* TCP1, T-complex protein 1 subunit alpha
* Chaperonin
HSP60, also known as chaper ...
* CESK1
* HSPD1
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 comp ...
* KCNMB3L
* CCT8L1; LOC401329
* MKKS
McKusick–Kaufman/Bardet–Biedl syndromes putative chaperonin is a 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 ...
* PIP5K3
See also
* Chaperone
* 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 ...
* Arthur L. Horwich
Notes
References
External links
more details...
*
cpnDB: a chaperonin database
NIH Material on HSP60
HSP60
The Protein Data Bank
Enzyme Database on HSP60
HSP60 on Pub Med
HSP60 Gene Report
*
{{Chaperones
Heat shock proteins
Moonlighting proteins
Molecular chaperones
Protein folding