Abstract
In E. coli cells, rescue of non-native proteins and promotion of native state structure is assisted by the chaperonin GroEL. An important key to this activity lies in the structure of the apical domain of GroEL (GroEL-AD) (residue 191–376), which recognizes and binds non-native protein molecules through hydrophobic interactions. In this study, we investigated the effects of GroEL-AD on the aggregation of various client proteins (α-Synuclein, Aβ42, and GroES) that lead to the formation of distinct protein fibrils in vitro. We found that GroEL-AD effectively inhibited the fibril formation of these three proteins when added at concentrations above a critical threshold; the specific ratio differed for each client protein, reflecting the relative affinities. The effect of GroEL-AD in all three cases was to decrease the concentration of aggregate-forming unfolded client protein or its early intermediates in solution, thereby preventing aggregation and fibrillation. Binding affinity assays revealed some differences in the binding mechanisms of GroEL-AD toward each client. Our findings suggest a possible applicability of this minimal functioning derivative of the chaperonins (the “minichaperones”) as protein fibrillation modulators and detectors.
Highlights
In E. coli cells, rescue of non-native proteins and promotion of native state structure is assisted by the chaperonin GroEL
Each client protein has been confirmed to form amyloid fibrils. α-Synuclein has been implicated in the pathogenesis of PD42–45 and Aβ42 deposits are correlated with the onset of AD46–48
In order to determine the existence of a similar role for chaperonins, we have examined the effects of GroEL-Alzheimer’s disease (AD), the apical domain fragment of the group I chaperonin GroEL from E. coli, on the aggregation of multiple client proteins which form amyloid fibrils
Summary
In E. coli cells, rescue of non-native proteins and promotion of native state structure is assisted by the chaperonin GroEL. Extensive studies to probe the underlying mechanism of amyloid fibril formation have been performed with a view to achieving an eventual methodology to prevent the production of cytotoxic molecular species[14,15,16,17,18]. In line with this objective, many instances have been reported where various molecular chaperones, an endogenous group of proteins known to interact with proteins and prevent their aggregation, have interacted to suppress or modulate the formation of amyloids. That GroEL is capable of recognizing and binding to various polypeptides implicated in amyloid-related diseases; NMR studies have shown explicitly that Aβpeptide[38] and α-Synuclein[39] are both recognized by the apical domain of GroEL and are bound at specific sites
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