In molecular biology, molecular chaperones are proteins 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 nucleosomes from folded histones and DNA and such assembly chaperones, especially in the nucleus,[1][2] are concerned with the assembly of folded subunits into oligomeric structures.[3]
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 proteins 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.
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Many chaperones are heat shock proteins, that is, proteins expressed in response to elevated temperatures or other cellular stresses.[4] The reason for this behaviour is that protein folding 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 may be important in chaperone function. The crowded environment of the cytosol can accelerate the folding process, since a compact folded protein will occupy less volume than an unfolded protein chain.[5] However, crowding can reduce the yield of correctly-folded protein by increasing protein aggregation.[6][7] Crowding may also increase the effectiveness of the chaperone proteins such as GroEL,[8] which could counteract this reduction in folding efficiency.[9]
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 chaperonins. 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, for example membranes of the mitochondria and endoplasmic reticulum (ER) in eukaryotes. Bacterial translocation—specific chaperone[10] maintains newly synthesized precursor polypeptide chains in a translocation-competent (generally unfolded) state and guides them to the translocon.
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).
Chaperones are found in, for example, the endoplasmic reticulum (ER), since protein synthesis often occurs in this area.
In the endoplasmic reticulum (ER) there are general, lectin- and non-classical molecular chaperones helping to fold proteins.
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 protein" has historically been used to name these chaperones. The prefix "Hsp" designates that the protein is a heat shock protein.
Hsp60 (GroEL/GroES complex in E. coli) is the best characterized large (~ 1 MDa) chaperone complex. GroEL 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 in its lumen. GroES 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.[14] Also acts in mitochondrial matrix as molecular chaperone.
Hsp70 (DnaK in E. coli) is perhaps the best characterized small (~ 70 kDa) chaperone.
The Hsp70 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.
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, and a low-affinity state when bound to ATP.
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.[15] Hsp70 also acts as a mitochondrial and chloroplastic molecular chaperone in eukaryotes.
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, and a dimerization 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.[16][17]
Hsp90 may also require co-chaperones-like immunophilins, Sti1, p50 (Cdc37), and Aha1, and also cooperates with the Hsp70 chaperone system.[18][19]
Hsp100 (Clp family in E. coli) proteins have been studied in vivo and in vitro 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 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, is essential for the propagation of many yeast prions. Deletion of the HSP104 gene results in cells that are unable to propagate certain prions.
The investigation of chaperones has a long history.[20] 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.[21] The term was later extended by R. John Ellis in 1987 to describe proteins that mediated the post-translational assembly of protein complexes.[22] In 1988, it was realised that similar proteins mediated this process in both prokaryotes and eukaryotes.[23] The details of this process were determined in 1989, when the ATP-dependent protein folding was demonstrated in vitro.[24]
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