A Single Ring Is Sufficient for Productive Chaperonin-Mediated Folding In Vivo

Nielsen, Kåre Lehmann; Cowan, Nicholas J.

doi:10.1016/s1097-2765(00)80117-3

Cited by 130 publications

(154 citation statements)

References 30 publications

(16 reference statements)

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“…However, Hsp10 interacts stably with Hsp60 in the presence, but not in the absence, of ATP or ADP (47,49,66,67). The observed binding of Hsp10 to mtHsp70 occurred without the addition of nucleotides and was lost in the presence of ATP (Fig.…”

Section: Mthsp70mentioning

confidence: 89%

“…Mitochondrial Hsp60 exists in single and double ring conformations, with one ring being composed of seven subunits (45)(46)(47)(48). Detailed structural and mechanistic insights have been obtained for the bacterial counterpart GroEL and its Hsp10 homolog GroES (1,3).…”

mentioning

confidence: 99%

“…The activity of the Hsp60 rings is driven by ATP-dependent conformational changes of the Hsp60 monomers. The heptameric Hsp10 ring forms the lid of the cavity and regulates the ATP-dependent reaction cycle of Hsp60 (47,49,50). Although Hsp60 is essential for cell survival (51), the assembly of the ring structures is poorly understood.…”

mentioning

confidence: 99%

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Mitochondrial Heat Shock Protein (Hsp) 70 and Hsp10 Cooperate in the Formation of Hsp60 Complexes

Böttinger

Oeljeklaus

Guiard

et al. 2015

Journal of Biological Chemistry

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Section: Mthsp70mentioning

confidence: 89%

mentioning

confidence: 99%

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Mitochondrial Heat Shock Protein (Hsp) 70 and Hsp10 Cooperate in the Formation of Hsp60 Complexes

Böttinger

Oeljeklaus

Guiard

et al. 2015

Journal of Biological Chemistry

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“…The mitochondrial Hsp60 (mHsp60) 3 is similar to GroEL in that it is made up of heptameric rings (12-14) that can refold denatured substrates in vitro with the assistance of a co-chaperonin and ATP (15). However, the mHsp60 oligomer is less stable than the bacterial homolog, and it exhibits unique nucleotide binding properties and specificity for co-chaperonin (13,14,16).In addition to their essential function in mediating protein folding, the mammalian mitochondrial chaperonins were also suggested to be involved in extramitochondrial activities. A number of reports have suggested that mHsp60 can stimulate human leukocytes and vascular endothelial cells to produce proinflammatory cytokines (17).…”

mentioning

confidence: 99%

“…The mitochondrial Hsp60 (mHsp60) 3 is similar to GroEL in that it is made up of heptameric rings (12)(13)(14) that can refold denatured substrates in vitro with the assistance of a co-chaperonin and ATP (15). However, the mHsp60 oligomer is less stable than the bacterial homolog, and it exhibits unique nucleotide binding properties and specificity for co-chaperonin (13,14,16).…”

mentioning

confidence: 99%

The MitCHAP-60 Disease Is Due to Entropic Destabilization of the Human Mitochondrial Hsp60 Oligomer

Parnas

Nadler

Nisemblat

et al. 2009

Journal of Biological Chemistry

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The 60-kDa heat shock protein (mHsp60) is a vital cellular complex that mediates the folding of many of the mitochondrial proteins. Its function is executed in cooperation with the cochaperonin, mHsp10, and requires ATP. Recently, the discovery of a new mHsp60-associated neurodegenerative disorder, Mit-CHAP-60 disease, has been reported. The disease is caused by a point mutation at position 3 (D3G) of the mature mitochondrial Hsp60 protein, which renders it unable to complement the deletion of the homologous bacterial protein in Escherichia coli (Magen, D., Georgopoulos, C., Bross, P., Ang, D., Segev, Y., Goldsher, D., Nemirovski, A., Shahar, E., Ravid, S., Luder, A., Heno, B., Gershoni-Baruch, R., Skorecki, K., and Mandel, H. (2008) Am. J. Hum. Genet. 83, 30 -42). The molecular basis of the MitCHAP-60 disease is still unknown. In this study, we present an in vitro structural and functional analysis of the purified wild-type human mHsp60 and the MitCHAP-60 mutant. We show that the D3G mutation leads to destabilization of the mHsp60 oligomer and causes its disassembly at low protein concentrations. We also show that the mutant protein has impaired protein folding and ATPase activities. An additional mutant that lacks the first three amino acids (N-del), including Asp-3, is similarly impaired in refolding activity. Surprisingly, however, this mutant exhibits profound stabilization of its oligomeric structure. These results suggest that the D3G mutation leads to entropic destabilization of the mHsp60 oligomer, which severely impairs its chaperone function, thereby causing the disease.Type I chaperonins are essential molecular chaperones of the Hsp60 family found in eubacteria, mitochondria, and chloroplasts (1). They are key players in mediating the correct folding of newly translated, translocated, and stress-denatured proteins. The folding function of chaperonins is executed by the coordinated action of two oligomeric proteins, Hsp60 (also named cpn60 and in bacteria GroEL) and its co-chaperonin Hsp10 (also named cpn10 and in bacteria GroES). The GroEL molecule is composed of 14 subunits that form a barrel-like structure that consists of two back-to-back stacked heptameric rings with a large cavity at each end termed the "Anfinsen cage." GroES is a heptameric ring formed by ϳ10-kDa subunits. The co-chaperonin binds to the chaperonin in the presence of ATP and Mg 2ϩ via a short, unstructured, but highly conserved region known as the mobile loop (2, 3). Due to the stability of the GroEL/ES oligomers and the ease with which they can be purified from bacteria, they have become the primary targets for study in the field of chaperonins. As a result, almost all of our knowledge concerning the structure and mechanism of chaperonins, both Hsp60 and Hsp10, is based largely on data from experiments on these E. coli proteins. The chaperonin reaction cycle starts when a non-folded protein substrate binds to the surface of the cavity of one of the GroEL rings. ATP-dependent GroES binding to that (cis) ring causes a dramatic co...

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Protein Interaction and Genetic Disease

Gregersen

Bross

Olsen

et al. 2011

Encyclopedia of Life Sciences

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The function of proteins is dependent on other proteins. Proteins function as oligomers, complexes, super‐complexes or higher order networks, in which they interact with each other, either temporarily when they exert their function or ‘permanently’ in functional units. Genetic defects in single proteins may therefore, in addition to disturbing the specific function of the defective protein, disturb other functions that are dependent on it. In this review we will discuss how the two main types of defects in genetic disease, truncating variations (stop‐codon introductions and small out‐of‐frame deletions/insertions) and in‐frame variations (missense variations and small in‐frame deletions/insertions), may disturb normal interactions. Depending on the importance (location) of the missing or aberrant protein, the effect on the cellular pathway or interacting network may be severe or mild. Protein interactions and disturbances therein may be determined by protein mass spectrometry after immuno‐precipitation or other fractionation and separation methods. Key Concepts: Cellular proteins interact in oligomer and complex structures as well as in higher order networks. Protein interactions may be permanent in the lifetime of proteins or temporary during their function. Genetic defects may disturb interactions between proteins depending on the nature of the defect and type of interaction. Missing proteins due to truncation, comprising big deletions, small out‐of‐frame deletions/insertions and severe splice alteration, may abolish the function of oligomers, complexes, pathways and networks. Aberrant proteins due to missense variations and in‐frame deletions/insertions may disturb interactions with protein partners in oligomers, complexes and networks. Missing and aberrant proteins in branch‐points (nodes) have as a role severe consequences, resulting in genotype–phenotype association. Missing and aberrant proteins in redundant pathways have variable consequences, resulting in poor genotype–phenotype association. Missing and aberrant proteins in molecular machines, such as the chaperonin Hsp60, may elicit pleotropic effects due to defective processing of client proteins. Protein interactions and disturbances therein may be determined experimentally by protein mass spectrometry (MS), preceded by immunoprecipitation of target proteins, either directly or after cross‐linking, or indicated after mild solubilisation followed by extensive separating procedures and MS. The challenge is to design experiments that can determine qualitative and quantitative disturbances of proteins interactions in cells and tissue from patients, model animals and model cells compared to interactions in normal cells and tissue.

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A Single Ring Is Sufficient for Productive Chaperonin-Mediated Folding In Vivo

Cited by 130 publications

References 30 publications

Mitochondrial Heat Shock Protein (Hsp) 70 and Hsp10 Cooperate in the Formation of Hsp60 Complexes

Mitochondrial Heat Shock Protein (Hsp) 70 and Hsp10 Cooperate in the Formation of Hsp60 Complexes

The MitCHAP-60 Disease Is Due to Entropic Destabilization of the Human Mitochondrial Hsp60 Oligomer

Protein Interaction and Genetic Disease

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