Chaperonins induce an amyloid-like transformation of ovine prion protein: The fundamental difference in action between eukaryotic TRiC and bacterial GroEL

Kiselev, Georgy G.; Naletova, Irina; Sheval, Eugene V.; Stroylova, Yulia Yu.; Schmalhausen, E.V.; Haertlé, Thomas; Muronetz, Vladimir I.

doi:10.1016/j.bbapap.2011.08.006

Cited by 17 publications

(12 citation statements)

References 32 publications

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“…It was previously suggested that the interaction of the infectious PrP with the bacterial chaperonin GroEL, which occurs in the gastrointestinal tract, is the key stage of the spongiform encephalopathies transmission [ 18 ]. The co-incubation of GroEL and PrP leads to the formation of protein aggregates, as demonstrated by the DLS turbidity study [ 18 ] and Immunoblot [ 19 ]. The presence of Mg–ATP was not required, but accelerated the reaction.…”

Section: Introductionmentioning

confidence: 99%

“…Earlier studies suggested that chaperonin on its own cannot convert PrP C to PrP Sc without the initial presence of small amounts of PrPSc [ 20 ]. However, more recent studies have shown that this conversion is possible [ 18 , 21 , 22 ]. Interestingly, GroEL can also exhibit “anti-chaperone” activity: upon the interaction of GroEL with a denatured PrP, the resulting aggregates are more stable than upon the interaction with a structured PrP [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Structural and Computational Study of the GroEL–Prion Protein Complex

et al. 2021

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The molecular chaperone GroEL is designed to promote protein folding and prevent aggregation. However, the interaction between GroEL and the prion protein, PrPC, could lead to pathogenic transformation of the latter to the aggregation-prone PrPSc form. Here, the molecular basis of the interactions in the GroEL–PrP complex is studied with cryo-EM and molecular dynamics approaches. The obtained cryo-EM structure shows PrP to be bound to several subunits of GroEL at the level of their apical domains. According to MD simulations, the disordered N-domain of PrP forms much more intermolecular contacts with GroEL. Upon binding to the GroEL, the N-domain of PrP begins to form short helices, while the C-domain of PrP exhibits a tendency to unfold its α2-helix. In the absence of the nucleotides in the system, these processes are manifested at the hundred nanoseconds to microsecond timescale.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural and Computational Study of the GroEL–Prion Protein Complex

et al. 2021

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“…At the same time, the role of amyloid fibrils in pathology of the nervous tissue should not be underestimated. It is known that chaperones, as well as some other biomacromolecules, are capable of disrupting amyloid fibrils to oligomers and smaller aggregates . Some synthetic molecules have also demonstrated a disaggregating effect on amyloid plaques .…”

Section: Introductionmentioning

confidence: 99%

Disruption of Amyloid Prion Protein Aggregates by Cationic Pyridylphenylene Dendrimers

Сорокина

Stroylova

Shifrina

et al. 2015

Macromolecular Bioscience

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Disruption of amyloid protein aggregates is one of the potential therapies for treatment of neurodegenerative disorders such as prion diseases. Here, for the first time we report that pH-independent cationic pyridylphenylene dendrimers are able to disrupt amyloid protein aggregates at physiological pH as exemplified by inclusion bodies of ovine prion protein. The results show that exposure of inclusion bodies to the dendrimers leads to its partial disaggregation and release of the nanosize protein-dendrimer complexes. The complexes were characterized by SDS PAGE, DLS, and Western blotting methods. Thioflavin T fluorescence clearly demonstrated a decrease of amyloidogenic capability of the prion protein upon exposure to the dendrimers. The complexes formed are stable and do not show further aggregation.

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“… 27 When mixed with ovine PrP, GroEL induces similar conformational changes and aggregation which has led to the suggestion that host protein interactions with gut flora could play a role in prion disease induction. 28 Gram negative bacteria LPS has also been shown to cause recombinant PrP to increase in beta sheet content which is more similar to the structure of PrP Sc . 29 It is possible that normal PrP C in the samples sent for BSE surveillance testing are interacting with bacterial components resulting in altered conformations which are more difficult to denature and/or degrade causing low level reactivity on certain PK dependant BSE surveillance tests.…”

Section: Discussionmentioning

confidence: 99%

Exploring the cause of initially reactive bovine brains on rapid tests for BSE

Dudas

James²,

Anderson

et al. 2015

Prion

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Bovine spongiform encephalopathy (BSE) is an invariably fatal prion disease of cattle. The identification of the zoonotic potential of BSE prompted safety officials to initiate surveillance testing for this disease. In Canada, BSE surveillance is primarily focused on high risk cattle including animals which are dead, down and unable to rise, diseased or distressed. This targeted surveillance results in the submission of brain samples with a wide range of tissue autolysis and associated contaminants. These contaminants have the potential to interfere with important steps of surveillance tests resulting in initially positive test results requiring additional testing to confirm the disease status of the animal.The current tests used for BSE screening in Canada utilize the relative protease resistance of the prion protein gained when it misfolds from PrPC to PrPSc as part of the disease process. Proteinase K completely digests PrPC in normal brains, but leaves most of the PrPSc in BSE positive brains intact which is detected using anti-prion antibodies. These tests are highly reliable but occasionally give rise to initially reactive/false positive results. Test results for these reactive samples were close to the positive/negative cut-off on a sub set of test platforms. This is in contrast to all of the previous Canadian positive samples whose numeric values on these same test platforms were 10 to 100 fold greater than the test positive/negative cut-off. Here we explore the potential reason why a sample is repeatedly positive on a sub-set of rapid surveillance tests, but negative on other test platforms.In order to better understand and identify what might cause these initial reactions, we have conducted a variety of rapid and confirmatory assays as well as bacterial isolation and identification on BSE positive, negative and initially reactive samples. We observed high levels of viable bacterial contamination in initially reactive samples suggesting that the reactivity may be related to bacterial factors. Several bacteria isolated from the initially reactive samples have characteristics of biofilm forming bacteria and this extracellular matrix might play a role in preventing complete digestion of PrPC in these samples.

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Chaperonins induce an amyloid-like transformation of ovine prion protein: The fundamental difference in action between eukaryotic TRiC and bacterial GroEL

Cited by 17 publications

References 32 publications

Structural and Computational Study of the GroEL–Prion Protein Complex

Structural and Computational Study of the GroEL–Prion Protein Complex

Disruption of Amyloid Prion Protein Aggregates by Cationic Pyridylphenylene Dendrimers

Exploring the cause of initially reactive bovine brains on rapid tests for BSE

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