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

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.

Functional amyloids from bacterial biofilms – structural properties and interaction partners

“…6, 48,152 similar to HET-s and the recently determined structure of a HET-s homolog HELLF functional amyloid fibrils. 99,153 The model is consistent with the repeats identified for CsgA, Fig. 2.…”

Aggregation-Prone Structural Ensembles of Transthyretin Collected With Regression Analysis for NMR Chemical Shift

“…This is attributed to the highly heterogeneous and dynamic structural states of proteins in their aggregation-prone states ( Kelly, 1996 ; Yang et al, 2021 ). To overcome these challenges, NMR spectroscopy ( Daskalov et al, 2021 ; Dyson and Wright, 2021 ) and MD simulation techniques ( Prabakaran et al, 2021 ; Strodel, 2021 ) are the two major methodologies that significantly contributed to advancing our understanding of the aggregation and amyloidosis mechanisms of various proteins. Indeed, NMR spectroscopy has been a major technique for investigating the mobile structural features of IDPs and amyloidogenic proteins, such as amyloid beta ( Crescenzi et al, 2002 ), tau ( Mukrasch et al, 2009 ), and α-synuclein ( Ulmer et al, 2005 ).…”

Methodological advances and strategies for high resolution structure determination of cellular protein aggregates

“…Thus, it has been used to discern the atomic-level structure of proteins in high molecular weight complexes, both in vivo and in vitro ( 92 ). In the field of protein aggregation, ssNMR has been used to elucidate molecular mechanisms and determine high resolution structures of disease fibrils, IBs, and functional aggregates ( 34 , 93 , 94 ). This section will summarize key advances, methods, and prospects of ssNMR for characterizing cellular aggregates, including disease amyloid proteins, prions, IBs, functional amyloids, and secretory granules.…”