Bacterial Chaperones CsgE and CsgC Differentially Modulate Human α-Synuclein Amyloid Formation via Transient Contacts.

Erik Chorell,Margery L Evans,Fredrik Almqvist,Anna Götheson,Jörgen Åden,Matthew R Chapman,Pernilla Wittung-Stafshede,Neha Jain,Emma Andersson,Ilia V Baskakov

doi:10.1371/journal.pone.0140194

Abstract

Amyloid formation is historically associated with cytotoxicity, but many organisms produce functional amyloid fibers (e.g., curli) as a normal part of cell biology. Two E. coli genes in the curli operon encode the chaperone-like proteins CsgC and CsgE that both can reduce in vitro amyloid formation by CsgA. CsgC was also found to arrest amyloid formation of the human amyloidogenic protein α-synuclein, which is involved in Parkinson’s disease. Here, we report that the inhibitory effects of CsgC arise due to transient interactions that promote the formation of spherical α-synuclein oligomers. We find that CsgE also modulates α-synuclein amyloid formation through transient contacts but, in contrast to CsgC, CsgE accelerates α-synuclein amyloid formation. Our results demonstrate the significance of transient protein interactions in amyloid regulation and emphasize that the same protein may inhibit one type of amyloid while accelerating another.

Highlights

Amyloid fibrils are β-sheet rich protein structures associated with human neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases [1]
When CsgE was added to α-synuclein aggregation reactions at a 1-to-10 molar ratio of CsgE to α-synuclein, the lag phase of α-synuclein amyloid formation was reduced by a factor of four (Fig 1A)
Atomic force microscopy (AFM) analysis revealed amyloid-like fibrils when α-synuclein was incubated alone or in the presence of CsgE (Fig 1D and 1E)

Summary

Introduction

Amyloid fibrils are β-sheet rich protein structures associated with human neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases [1]. The common structural element of these fibrils is the cross-β conformation; i.e., β-sheets that are packed perpendicular to the fiber axis. Most amyloid fibrils form via nucleation-dependent pathways that involve oligomeric, pre-fibrillar structures [2]. Α-Synuclein is a 140-residue protein involved in Parkinsons disease, a condition which affects 2% of the population older than 60 years [3]. It is an intrinsically unstructured protein that adopts α-helical structure in the presence of vesicles or membranes [4]. Residues 60 to 95 in the α-synuclein primary sequence (the so called NAC region) constitute the primary aggregation-promoting region [4] whereas the acidic C-terminal part

Methods

Results

Conclusion