Structures of Pathological and Functional Amyloids and Prions, a Solid-State NMR Perspective.

Gaelle Lamon,Sven J Saupe,Melanie Berbon,Axelle Grélard,Yann Fichou,Denis Martinez,Alons Lends,Asen Daskalov,Mathias Ferber,Antoine Loquet,Jayakrishna Shenoy,Birgit Habenstein,Brice Kauffmann,Benjamin Bardiaux,Ahmad Saad,Estelle Morvan,Nadia El Mammeri

doi:10.3389/fnmol.2021.670513

Abstract

Infectious proteins or prions are a remarkable class of pathogens, where pathogenicity and infectious state correspond to conformational transition of a protein fold. The conformational change translates into the formation by the protein of insoluble amyloid aggregates, associated in humans with various neurodegenerative disorders and systemic protein-deposition diseases. The prion principle, however, is not limited to pathogenicity. While pathological amyloids (and prions) emerge from protein misfolding, a class of functional amyloids has been defined, consisting of amyloid-forming domains under natural selection and with diverse biological roles. Although of great importance, prion amyloid structures remain challenging for conventional structural biology techniques. Solid-state nuclear magnetic resonance (SSNMR) has been preferentially used to investigate these insoluble, morphologically heterogeneous aggregates with poor crystallinity. SSNMR methods have yielded a wealth of knowledge regarding the fundamentals of prion biology and have helped to solve the structures of several prion and prion-like fibrils. Here, we will review pathological and functional amyloid structures and will discuss some of the obtained structural models. We will finish the review with a perspective on integrative approaches combining solid-state NMR, electron paramagnetic resonance and cryo-electron microscopy, which can complement and extend our toolkit to structurally explore various facets of prion biology.

Highlights

Prions are infectious proteins, representing the most recently uncovered category of pathogens (Prusiner, 1982)
On the basis of Solid-state nuclear magnetic resonance (SSNMR) data (Figures 4D,E), we proposed that the NWD2 segment 3–23 adopts the same structure as a single prionforming domain (PFD) repeat of HET-s (Daskalov et al, 2015b)
In the past two decades, methodological advances in solid-state NMR spectroscopy have led to the development of efficient biophysical techniques to extract structural and dynamics information of protein aggregates

Summary

INTRODUCTION

Prions are infectious proteins, representing the most recently uncovered category of pathogens (Prusiner, 1982). The prion principle (the emergence and self-propagation of a protein state) is not exclusively associated with misfolded proteins causing pathologies (see Figure 1) but underlies various physiologically important cellular processes like long-term memory consolidation and antiviral innate immunity in animals (Hou et al, 2011; Cai et al, 2014; Si and Kandel, 2016) Such protein-based phenomena are associated to the emergence of so-called functional amyloids (Rayman and Kandel, 2017; Loquet et al, 2018b) and have been proposed to play a role in an epigenetic control of flowering in plants (Chakrabortee et al, 2016). Cross-β patterns are a diagnostic hallmark of amyloid, any structural information leading to high-resolution structures is limited due to the difficulty in growing highly ordered crystals from amyloid fibrils due to their polymorphic nature, and to provide the tertiary and quaternary arrangement that can be very different among amyloid aggregates

A Long Quest for the High-Resolution Structure of Pathological Amyloids

CONCLUSION