Abstract
Amyloid proteins are involved in many neurodegenerative disorders such as Alzheimer’s disease [Tau, Amyloid β (Aβ)], Parkinson’s disease [alpha-synuclein (αSyn)], and amyotrophic lateral sclerosis (TDP-43). Driven by the early observation of the presence of ordered structure within amyloid fibrils and the potential to develop inhibitors of their formation, a major goal of the amyloid field has been to elucidate the structure of the amyloid fold at atomic resolution. This has now been achieved for a wide variety of sequences using solid-state NMR, microcrystallography, X-ray fiber diffraction and cryo-electron microscopy. These studies, together with in silico methods able to predict aggregation-prone regions (APRs) in protein sequences, have provided a wealth of information about the ordered fibril cores that comprise the amyloid fold. Structural and kinetic analyses have also shown that amyloidogenic proteins often contain less well-ordered sequences outside of the amyloid core (termed here as flanking regions) that modulate function, toxicity and/or aggregation rates. These flanking regions, which often form a dynamically disordered “fuzzy coat” around the fibril core, have been shown to play key parts in the physiological roles of functional amyloids, including the binding of RNA and in phase separation. They are also the mediators of chaperone binding and membrane binding/disruption in toxic amyloid assemblies. Here, we review the role of flanking regions in different proteins spanning both functional amyloid and amyloid in disease, in the context of their role in aggregation, toxicity and cellular (dys)function. Understanding the properties of these regions could provide new opportunities to target disease-related aggregation without disturbing critical biological functions.
Highlights
In the 60 years since the first atomic structure of the protein myoglobin was solved using X-ray diffraction of protein crystals (Kendrew et al, 1960), the field of structural biology has been dominated by the study of globular proteins with a well-defined tertiary structure, with more than 160,000 unique structures solved to date using crystallography, NMR or cryoEM (Geraets et al, 2020)
While more than 50 proteins are known to form amyloid associated with disease (Iadanza et al, 2018a; Benson et al, in press), here we focus on αSyn, TAR DNA-binding protein 43 (TDP-43), Amyloid β (Aβ), Tau, β2m, Orb2, and Prion Protein (PrP) as exemplars of intrinsically disordered proteins (IDPs), natively folded proteins, prions, and functional and disease related proteins
In this review we focus on the roles of regions that flank the aggregation-prone regions (APRs) and/or fibril cores in amyloid formation
Summary
In the 60 years since the first atomic structure of the protein myoglobin was solved using X-ray diffraction of protein crystals (Kendrew et al, 1960), the field of structural biology has been dominated by the study of globular proteins with a well-defined tertiary structure, with more than 160,000 unique structures solved to date using crystallography, NMR or cryoEM (Geraets et al, 2020). Despite this feat, more than 50% of the proteins in eukaryotes are known to have at least one long (>30 residues) sequence that is intrinsically disordered [intrinsically disordered regions. While more than 50 proteins are known to form amyloid associated with disease (Iadanza et al, 2018a; Benson et al, in press), here we focus on αSyn, TDP-43, Aβ, Tau, β2m, Orb, and PrP as exemplars of IDPs, natively folded proteins, prions, and functional and disease related proteins
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