GroEL

HSPD1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	4PJ1
Identifiers
Aliases	HSPD1, CPN60, GROEL, HLD4, HSP-60, HSP60, HSP65, HuCHA60, SPG13, heat shock protein family D (Hsp60) member 1
External IDs	OMIM: 118190 MGI: 96242 HomoloGene: 1626 GeneCards: HSPD1
Gene location (Human)
Chr.	Chromosome 2 (human)[1]
End	197,516,737 bp[1]
Gene location (Mouse)
Chr.	Chromosome 1 (mouse)[2]
End	55,088,243 bp[2]
RNA expression pattern
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	• nucleotide binding; • chaperone binding; • p53 binding; • single-stranded DNA binding; • ATPase activity; • GO:0001948 protein binding; • double-stranded RNA binding; • DNA replication origin binding; • ATP binding; • ubiquitin protein ligase binding; • protein binding involved in protein folding; • unfolded protein binding; • RNA binding; • hydrolase activity; • high-density lipoprotein particle binding; • enzyme binding; • apolipoprotein binding; • apolipoprotein A-I binding; • lipopolysaccharide binding; • isomerase activity;
Cellular component	• cytoplasm; • cyclin-dependent protein kinase activating kinase holoenzyme complex; • protein complex; • lipopolysaccharide receptor complex; • early endosome; • mitochondrion; • clathrin-coated pit; • coated vesicle; • extracellular exosome; • extracellular matrix; • mitochondrial matrix; • extracellular; • mitochondrial inner membrane; • cytosol; • cell membrane; • cell surface; • membrane; • secretory granule; • macromolecular complex;
Biological process	• chaperone-mediated protein complex assembly; • positive regulation of interleukin-12 production; • positive regulation of interleukin-10 production; • protein stabilization; • protein maturation; • positive regulation of macrophage activation; • MyD88-dependent toll-like receptor signaling pathway; • isotype switching to IgG isotypes; • B cell activation; • B cell cytokine production; • response to unfolded protein; • B cell proliferation; • protein folding; • positive regulation of T cell mediated immune response to tumor cell; • protein refolding; • positive regulation of interleukin-6 production; • positive regulation of apoptotic process; • response to cold; • viral process; • activation of cysteine-type endopeptidase activity involved in apoptotic process; • regulation of transcription from RNA polymerase II promoter; • 'de novo' protein folding; • protein import into mitochondrial intermembrane space; • chaperone-mediated protein folding; • apoptotic mitochondrial changes; • positive regulation of interferon-alpha production; • positive regulation of interferon-gamma production; • T cell activation; • negative regulation of apoptotic process; • positive regulation of T cell activation; • mitochondrion organization;
	Sources:Amigo / QuickGO
Orthologs
	3329
	15510
	ENSG00000144381
	ENSMUSG00000025980
	P10809
	P63038
	NM_002156; NM_199440
	NM_010477; NM_001356512
	NP_002147; NP_955472
	NP_034607; NP_001343441
	Wikidata
View/Edit Human	View/Edit Mouse

GroEL is a protein which belongs to the chaperonin family of molecular chaperones, and is found in many bacteria.[5] It is required for the proper folding of many proteins. To function properly, GroEL requires the lid-like cochaperonin protein complex GroES. In eukaryotes the proteins Hsp60 and Hsp10 are structurally and functionally nearly identical to GroEL and GroES, respectively.

Mechanism

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.[6]

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.

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 apical section contains many hydrophobic binding sites for unfolded protein substrates. Many globular proteins won't bind to the apical domain because their hydrophobic parts are clustered inside, away from the aqueous medium since this is the thermodynamically optimal conformation. Thus, these "substrate sites" will only bind to proteins which are not optimally folded. The apical domain also has binding sites for the Hsp10 monomers of GroES.

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 flexion and rotation at the two hinge points on the Hsp60 monomers. The intermediate domain folds down and inward about 25° on the lower hinge. This effect, multiplied through the cooperative flexing of all monomers, increases the equatorial diameter of the GroEL cage. But the apical domain rotates a full 60° up and out on the upper hinge, and also rotates 90° around the hinge axis. This motion opens the cage very widely at the top of the cis domain, but completely removes the substrate binding sites from the inside of the cage.

Interactions

GroEL has been shown to interact with GroES,[7][8] ALDH2,[8] Caspase 3[7][9] and Dihydrofolate reductase.[10]

References

GRCh38: Ensembl release 89: ENSG00000144381 - Ensembl, May 2017
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.
Zeilstra-Ryalls J, Fayet O, Georgopoulos C (1991). "The universally conserved GroE (Hsp60) chaperonins". Annu. Rev. Microbiol. 45: 301–25. doi:10.1146/annurev.mi.45.100191.001505. PMID 1683763.
Horwich AL, Fenton WA, Chapman E, Farr GW (2007). "Two families of chaperonin: physiology and mechanism". Annu. Rev. Cell Dev. Biol. 23: 115–45. doi:10.1146/annurev.cellbio.23.090506.123555. PMID 17489689.
Samali A, Cai J, Zhivotovsky B, Jones DP, Orrenius S (Apr 1999). "Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells". EMBO J. 18 (8): 2040–8. doi:10.1093/emboj/18.8.2040. PMC 1171288. PMID 10205158.
Lee KH, Kim HS, Jeong HS, Lee YS (Oct 2002). "Chaperonin GroESL mediates the protein folding of human liver mitochondrial aldehyde dehydrogenase in Escherichia coli". Biochem. Biophys. Res. Commun. 298 (2): 216–24. doi:10.1016/S0006-291X(02)02423-3. PMID 12387818.
Xanthoudakis S, Roy S, Rasper D, Hennessey T, Aubin Y, Cassady R, Tawa P, Ruel R, Rosen A, Nicholson DW (Apr 1999). "Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis". EMBO J. 18 (8): 2049–56. doi:10.1093/emboj/18.8.2049. PMC 1171289. PMID 10205159.
Mayhew M, da Silva AC, Martin J, Erdjument-Bromage H, Tempst P, Hartl FU (Feb 1996). "Protein folding in the central cavity of the GroEL-GroES chaperonin complex". Nature. 379 (6564): 420–6. doi:10.1038/379420a0. PMID 8559246.

External links

GroEL+Protein at the US 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

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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000144381 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000025980 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[Zeilstra-Ryalls-5] Zeilstra-Ryalls J, Fayet O, Georgopoulos C (1991). "The universally conserved GroE (Hsp60) chaperonins". Annu. Rev. Microbiol. 45: 301–25. doi:10.1146/annurev.mi.45.100191.001505. PMID 1683763.

[Horwhich-6] Horwich AL, Fenton WA, Chapman E, Farr GW (2007). "Two families of chaperonin: physiology and mechanism". Annu. Rev. Cell Dev. Biol. 23: 115–45. doi:10.1146/annurev.cellbio.23.090506.123555. PMID 17489689.

[pmid10205158-7] Samali A, Cai J, Zhivotovsky B, Jones DP, Orrenius S (Apr 1999). "Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells". EMBO J. 18 (8): 2040–8. doi:10.1093/emboj/18.8.2040. PMC 1171288. PMID 10205158.

[pmid12387818-8] Lee KH, Kim HS, Jeong HS, Lee YS (Oct 2002). "Chaperonin GroESL mediates the protein folding of human liver mitochondrial aldehyde dehydrogenase in Escherichia coli". Biochem. Biophys. Res. Commun. 298 (2): 216–24. doi:10.1016/S0006-291X(02)02423-3. PMID 12387818.

[pmid10205159-9] Xanthoudakis S, Roy S, Rasper D, Hennessey T, Aubin Y, Cassady R, Tawa P, Ruel R, Rosen A, Nicholson DW (Apr 1999). "Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis". EMBO J. 18 (8): 2049–56. doi:10.1093/emboj/18.8.2049. PMC 1171289. PMID 10205159.

[pmid8559246-10] Mayhew M, da Silva AC, Martin J, Erdjument-Bromage H, Tempst P, Hartl FU (Feb 1996). "Protein folding in the central cavity of the GroEL-GroES chaperonin complex". Nature. 379 (6564): 420–6. doi:10.1038/379420a0. PMID 8559246.