Abstract
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.
Highlights
We present a cryo-EM structure of the initial GroEL–Prion Protein (PrP) complex and the results of molecular dynamics (MD) simulations to shed some light on the molecular basis of these interactions
Starting conformations of GroEL and PrP were chosen from a molecular dynamics simulation of two separated proteins, conducted by our group earlier [29,30]
The obtained cryo-EM map (Figure 1) contains an additional density in the apical domain region, in comparison to the apo GroEL structures. This additional density is attributed to Prp and its contacts with the I helices of the GroEL apical domains
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The prokaryotic GroEL/GroES complex is the most studied chaperonin from the heat shock proteins (HSP) family. It interacts with non-native conformations of various proteins, preventing their incorrect folding and aggregation in an ATP-dependent manner [1]. The apical domain of GroEL interacts with substrate proteins and GroES, while the equatorial one binds the ATP [3]. A normal isoform of the prion protein exists that is termed PrPC (C-cellular) It is encoded by the highly conserved Prnp gene, consists of 253 amino acids, and is localized at the outer layer of the plasma membrane [13]. We present a cryo-EM structure of the initial GroEL–PrP complex and the results of molecular dynamics (MD) simulations to shed some light on the molecular basis of these interactions
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