GroEL
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| Location (UCSC) | Chr 2: 197.49 – 197.52 Mb | Chr 1: 55.12 – 55.13 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
 | This article is missing information about action in bacteria and chloroplasts. (December 2020) |
GroEL is a protein which belongs to the
HSP60 is implicated in mitochondrial protein import and macromolecular assembly. It may facilitate the correct folding of imported proteins, and may also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix. HSP60 interacts with HRAS and with HBV protein X and HTLV-1 protein p40tax. HSP60 belongs to the chaperonin (HSP60) family. Note: This description may include information from UniProtKB.
Alternate Names: 60 kDa chaperonin, Chaperonin 60, CPN60, Heat shock protein 60, HSP-60, HuCHA60, Mitochondrial matrix protein P1, P60 lymphocyte protein, HSPD1
Heat shock protein 60 (HSP60) is a
Discovery
Not much is known about the function of HSP60.
Structure
Under normal physiological conditions, HSP60 is a 60 kilodalton oligomer composed of monomers that form a complex arranged as two stacked heptameric rings.
Each subunit of HSP60 has three
The mitochondrial HSP60
The predicted structure of HSP60 includes several vertical
Newer information has begun to suggest that the HSP60 found in the mitochondria differs from that of the cytoplasm. With respect to the amino acid sequence, the cytoplasmic HSP60 has an N-terminal sequence not found in the mitochondrial protein. In times of stress or high need of HSP60 in either the cytoplasm or the mitochondria, the cell is capable for compensating by increasing the presence of HSP60 in one compartment and decreasing its concentration in the opposite compartment.
Function
Common
Heat shock proteins are amongst the most
Mitochondrial protein transport
HSP60 possesses two main responsibilities with respect to mitochondrial protein transport. It functions to
DNA metabolism
In addition to its critical role in protein folding, HSP60 is involved in the replication and transmission of mitochondrial DNA. In extensive studies of HSP60 activity in Saccharomyces cerevisiae, scientists have proposed that HSP60 binds preferentially to the single stranded template DNA strand in a tetradecamer like complex [15]
This tetradecamer complex interacts with other transcriptional elements to serve as a regulatory mechanism for the replication and transmission of mitochondrial DNA. Mutagenic studies have further supported HSP60 regulatory involvement in the replication and transmission of mitochondrial DNA.
Cytoplasmic vs mitochondrial HSP60
In addition to the already illustrated structural differences between cytoplasmic and mitochondrial HSP60, there are marked functional differences. Studies have suggested that HSP60 plays a key role in preventing
Synthesis and assembly
HSP60 is typically found in the mitochondria and has been found in organelles of endosymbiotic origin. HSP60 monomers form two heptameric rings that bind to the surface of linear proteins and catalyze their folding in an ATP dependent process. There is a direct positive correlation between the presence of HSP60 proteins in the mitochondria and the production of additional HSP60 protein complexes.
The
Immunological role
As discussed above, HSP60 has generally been known as a chaperonin which assists in protein folding in mitochondria. However, some new research has indicated that HSP60 possibly plays a role in a “danger signal cascade”
There is however, a twist in the immunological role of HSP60. As mentioned above, there are two different types of HSP60 proteins, bacterial as well as mammalian. Since they are very similar in sequence, bacterial HSP60 wouldn’t be expected to cause a large immune response in humans. The immune system is “designed to ignore ‘self’, that is, host constituents; however, paradoxically, this is not the case with chaperonins”.
Stress response
HSP60, as a mitochondrial protein, has been shown to be involved in stress response as well. The heat shock response is a
Relationship to cancer
Human Hsp60, the product of the HSPD1 gene, is a Group I mitochondrial chaperonin, phylogenetically related to bacterial GroEL. Recently, the presence of Hsp60 outside the mitochondria and outside the cell, e.g. in circulating blood, has been reported [1], [2]. Although it is assumed that Hsp60 extra-mitochondrial molecule is identical to the mitochondrial one, this has not yet been fully elucidated. Despite the increasing amount of experimental evidences showing Hsp60 outside the cell, it is not yet clear how general this process is and what are the mechanisms responsible for Hsp60 translocation outside the cell. Neither of these questions has been definitively answered, whereas there is some information regarding extracellular Hsp70. This chaperone was also classically regarded as an intracellular protein like Hsp60, but in the last few years considerable evidences showed its pericellular and extracellular residence
HSP60 has been shown to influence
As well as influencing apoptosis, HSP60 changes in expression level have been shown to be “useful new biomarkers for diagnostic and prognostic purposes.”
Mechanism
| This article is missing information about different mechanisms between bacterial GroEL and HSPD1 -- HSPD1 has some wacky symmetrical intermediates. (December 2020) |
Within the cell, the process of GroEL/ES mediated protein folding involves multiple rounds of binding, encapsulation, and release of substrate protein. Unfolded substrate proteins bind to a hydrophobic binding patch on the interior rim of the open cavity of GroEL, forming a binary complex with the chaperonin. Binding of substrate protein in this manner, in addition to binding of ATP, induces a conformational change that allows association of the binary complex with a separate lid structure, GroES. Binding of GroES to the open cavity of the chaperonin induces the individual subunits of the chaperonin to rotate such that the hydrophobic substrate binding site is removed from the interior of the cavity, causing the substrate protein to be ejected from the rim into the now largely hydrophilic chamber. The hydrophilic environment of the chamber favors the burying of hydrophobic residues of the substrate, inducing substrate folding. Hydrolysis of ATP and binding of a new substrate protein to the opposite cavity sends an allosteric signal causing GroES and the encapsulated protein to be released into the cytosol. A given protein will undergo multiple rounds of folding, returning each time to its original unfolded state, until the native conformation or an intermediate structure committed to reaching the native state is achieved. Alternatively, the substrate may succumb to a competing reaction, such as misfolding and aggregation with other misfolded proteins.[26]
Thermodynamics
The constricted nature of the interior of the molecular complex strongly favors compact molecular conformations of the substrate protein. Free in solution, long-range, non-polar interactions can only occur at a high cost in entropy. In the close quarters of the GroEL complex, the relative loss of entropy is much smaller. The method of capture also tends to concentrate the non-polar binding sites separately from the polar sites. When the GroEL non-polar surfaces are removed, the chance that any given non-polar group will encounter a non-polar intramolecular site are much greater than in bulk solution. The hydrophobic sites which were on the outside are gathered together at the top of the cis domain and bind each other. The geometry of GroEL requires that the polar structures lead, and they envelop the non-polar core as it emerges from the trans side.
Structure
Structurally, GroEL is a dual-ringed tetradecamer, with both the cis and trans rings consisting of seven subunits each. The conformational changes that occur within the central cavity of GroEL cause for the inside of GroEL to become hydrophilic, rather than hydrophobic, and is likely what facilitates protein folding.
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GroEL (side) -
GroEL (top) -
GroES/GroEL complex (side) -
GroES/GroEL complex (top)
The key to the activity of GroEL is in the structure of the monomer. The Hsp60 monomer has three distinct sections separated by two hinge regions. The
The equatorial domain has a slot near the hinge point for binding ATP, as well as two attachment points for the other half of the GroEL molecule. The rest of the equatorial section is moderately hydrophilic.
The addition of ATP and GroES has a drastic effect on the conformation of the cis domain. This effect is caused by
Interactions
GroEL has been shown to
Phage T4 morphogenesis
The genes of bacteriophage (phage) T4 that encode proteins with a role in determining phage T4 structure were identified using conditional lethal mutants.[31] 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[32] identified a group of gps that act catalytically rather than being incorporated themselves into the phage structure. These catalytic gps included gp31. The bacterium E. coli is the host for phage T4, and the phage encoded gp31 protein appears to be functionally homologous to E. coli chaparone protein GroES and able to substitute for it in the assembly of phage T4 virions during infection.[5] The role of the phage encoded gp31 protein appears be to interact with the E. coli host encoded GroEL protein to assist in the correct folding and assembly of the major phage head capsid protein of the phage, gp23.[5]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000144381 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025980 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 1683763.
- ^ PMID 7752884.
- ^ PMID 12444982.
- S2CID 28394330.
- ^ S2CID 23840816.
- ^ S2CID 24067484.
- ^ S2CID 38110138.
- PMID 10329779.
- PMID 2575559.
- ^ S2CID 7430067.
- ^ Kaufman, BA. Studies on mitochondria DNA nucleoids in Saccharomyces cerevisiae: identification of bifunctional proteins. In Genetics and Development, UT Southwestern Medical Center at Dallas, Dallas, TX. 241pp.
- PMID 14597775.
- S2CID 7430067.
- PMID 12444982.
- ^ S2CID 25856774.
- S2CID 41092962.
- S2CID 6512400.
- PMID 12460802.
- ^ PMID 17048249.
- ^ PMID 17095522.
- ^ S2CID 30820581.
- PMID 17489689.
- ^ PMID 10205158.
- ^ PMID 12387818.
- PMID 10205159.
- S2CID 4310511.
- PMID 14272117.
- PMID 4878023.
Further reading
- Tabibzadeh S, Broome J (1999). "Heat shock proteins in human endometrium throughout the menstrual cycle". Infect Dis Obstet Gynecol. 7 (1–2): 5–9. PMID 10231001.
- Schäfer C, Williams JA (2000). "Stress kinases and heat shock proteins in the pancreas: possible roles in normal function and disease". J. Gastroenterol. 35 (1): 1–9. S2CID 9706591.
- Moseley P (2000). "Stress proteins and the immune response". Immunopharmacology. 48 (3): 299–302. PMID 10960671.
- Liu Y, Steinacker JM (2001). "Changes in skeletal muscle heat shock proteins: pathological significance". Front. Biosci. 6: D12-25. PMID 11145923.
- Van Maele B, Debyser Z (2005). "HIV-1 integration: an interplay between HIV-1 integrase, cellular and viral proteins". AIDS Rev. 7 (1): 26–43. PMID 15875659.
- Hochstrasser DF, Frutiger S, Paquet N, Bairoch A, Ravier F, Pasquali C, Sanchez JC, Tissot JD, Bjellqvist B, Vargas R (1992). "Human liver protein map: a reference database established by microsequencing and gel comparison". Electrophoresis. 13 (12): 992–1001. S2CID 23518983.
- Ikawa S, Weinberg RA (1992). "An interaction between p21ras and heat shock protein hsp60, a chaperonin". Proc. Natl. Acad. Sci. U.S.A. 89 (6): 2012–6. PMID 1347942.
- Brudzynski K, Martinez V, Gupta RS (1992). "Immunocytochemical localization of heat-shock protein 60-related protein in beta-cell secretory granules and its altered distribution in non-obese diabetic mice". Diabetologia. 35 (4): 316–24. PMID 1516759.
- Dawson SJ, White LA (1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". J. Infect. 24 (3): 317–20. PMID 1602151.
- Singh B, Patel HV, Ridley RG, Freeman KB, Gupta RS (1990). "Mitochondrial import of the human chaperonin (HSP60) protein". Biochem. Biophys. Res. Commun. 169 (2): 391–6. PMID 1972619.
- Venner TJ, Singh B, Gupta RS (1990). "Nucleotide sequences and novel structural features of human and Chinese hamster hsp60 (chaperonin) gene families". DNA Cell Biol. 9 (8): 545–52. PMID 1980192.
- Ward LD, Hong J, Whitehead RH, Simpson RJ (1990). "Development of a database of amino acid sequences for human colon carcinoma proteins separated by two-dimensional polyacrylamide gel electrophoresis". Electrophoresis. 11 (10): 883–91. S2CID 21541503.
- Jindal S, Dudani AK, Singh B, Harley CB, Gupta RS (1989). "Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen". Mol. Cell. Biol. 9 (5): 2279–83. PMID 2568584.
- Waldinger D, Eckerskorn C, Lottspeich F, Cleve H (1988). "Amino-acid sequence homology of a polymorphic cellular protein from human lymphocytes and the chaperonins from Escherichia coli (groEL) and chloroplasts (Rubisco-binding protein)". Biol. Chem. Hoppe-Seyler. 369 (10): 1185–9. PMID 2907406.
- Kreisel W, Hildebrandt H, Schiltz E, Köhler G, Spamer C, Dietz C, Mössner W, Heilmann C (1994). "Immuno-gold electron microscopical detection of heat shock protein 60 (hsp60) in mitochondria of rat hepatocytes and myocardiocytes". Acta Histochem. 96 (1): 51–62. PMID 7518175.
- Corbett JM, Wheeler CH, Baker CS, Yacoub MH, Dunn MJ (1994). "The human myocardial two-dimensional gel protein database: update 1994". Electrophoresis. 15 (11): 1459–65. S2CID 33359306.
- Baca-Estrada ME, Gupta RS, Stead RH, Croitoru K (1994). "Intestinal expression and cellular immune responses to human heat-shock protein 60 in Crohn's disease". Dig. Dis. Sci. 39 (3): 498–506. S2CID 22032288.
- Vélez-Granell CS, Arias AE, Torres-Ruíz JA, Bendayan M (1994). "Molecular chaperones in pancreatic tissue: the presence of cpn10, cpn60 and hsp70 in distinct compartments along the secretory pathway of the acinar cells". J. Cell Sci. 107 (3): 539–49. PMID 7911805.
- Mayhew M, da Silva AC, Martin J, Erdjument-Bromage H, Tempst P, Hartl FU (1996). "Protein folding in the central cavity of the GroEL-GroES chaperonin complex". Nature. 379 (6564): 420–6. S2CID 4310511.
- Tabibzadeh S, Kong QF, Satyaswaroop PG, Babaknia A (1996). "Heat shock proteins in human endometrium throughout the menstrual cycle". Hum. Reprod. 11 (3): 633–40. PMID 8671282.
External links
- GroEL+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- "Palaeos Bacteria: Pieces: GroEL". Archived from the original on 2007-04-26. (No rights reserved)
- 3D macromolecular structures of GroEL in EMDB