Inhibition of chaperonin GroEL by a monomer of ovine prion protein and its oligomeric forms

Abstract

The possibility of inhibition of chaperonin functional activity by amyloid proteins was studied. It was found that the ovine prion protein PrP as well as its oligomeric and fibrillar forms are capable of binding with the chaperonin GroEL. Besides, GroEL was shown to promote amyloid aggregation of the monomeric and oligomeric PrP as well as PrP fibrils. The monomeric PrP was shown to inhibit the GroEL-assisted reactivation of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The oligomers of PrP decelerate the GroEL-assisted reactivation of GAPDH, and PrP fibrils did not affect this process. The chaperonin GroEL is capable of interacting with GAPDH and different PrP forms simultaneously. A possible role of the inhibition of chaperonins by amyloid proteins in the misfolding of the enzymes involved in cell metabolism and in progression of neurodegenerative diseases of amyloid nature is discussed.

Structural and Computational Study of the GroEL–Prion Protein Complex

“…The resulting pellet was dissolved in SB and then dialyzed against it for 2 hrs. Chaperonin activity was also tested by chaperonedependent reactivation of denatured glyceraldehyde-3-phosphate dehydrogenase from rabbit muscle [23]. After that, 8 µM GroEL were co-incubated with 16 µM PrP in SB for 30 min at 21 • C. Formation of the GroEL-PrP complex was confirmed using dynamic light scattering (Figures S4 and S5).…”

“…Biochemical and biophysical studies (using ELISA, DLS, fluorescence analysis, etc.) [ 23 ] demonstrated the inhibition of GroEL activity by a monomer of the ovine prion protein and its oligomeric forms. Thus, the action of GroEL on PrP can lead to the onset of a pathological process; however, the underlying mechanism is poorly understood, in particular due to the lack of structural information.…”

Regulation by Different Types of Chaperones of Amyloid Transformation of Proteins Involved in the Development of Neurodegenerative Diseases

“…At the same time, the complex GroEL-GroES is also able to bind to monomers, toxic oligomers, protofibrils, and prion protein fibrils. The chaperonin GroEL-GroES in the presence of ATP promotes amyloid transformation of the monomeric and oligomeric forms of PrP but also results in partial disassembly of PrP amyloid fibrils [ 86 ]. However, the eukaryotic chaperonin TRiC, the apical domains of which perform a function of GroES, is not capable of disassembling oligomeric prion forms.…”

“…At the same time, mutant or infectious forms of prions can block chaperones, causing ER stress. Chaperones are involved in the destruction of already formed oligomeric and fibrillar forms of the prion protein [ 86 ]. In addition, bacterial chaperones may be involved in the transport of infectious forms of prions from the gut to the central nervous system, which will be discussed in more detail in the last section of the review.…”

“…Such binding decreases the flexibility of the chaperonin ring in which the prion protein is bound [ 85 ]. The interaction of PrPc with GroEL disturbs the functioning of the GroEL–GroES complex: the chaperonin loses its ability to reactivate denatured GAPDH [ 86 ]. The same effect was observed in experiments with the eukaryotic chaperonin TRiC.…”