Looking Beyond the Core: The Role of Flanking Regions in the Aggregation of Amyloidogenic Peptides and Proteins

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.

NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils

“…Flanking IDRs in amyloid fibrils of multiple proteins have been shown to regulate protein and membrane binding of functional amyloids, modulate aggregation kinetics, and may play important roles fibril growth and monomer recruitment (27, 70). The remarkable similarity in the monomer recognition site for PFFs and PFOs is at first surprising, given the vast difference in morphologies between the PFFs and PFOs.…”

“…These IDRs are a substantial fraction of the fibril structure and make up a “fuzzy coat” that surrounds the rigid core (19–21). The flexible flanking regions in several amyloid proteins have been found to be highly involved in biological interactions, including binding to receptors, chaperones, membranes, or RNA (27). In αS, modifying the “fuzzy coat” through pathologically relevant N- and C-terminal truncations was shown to modulate the aggregation and seeding propensity of αS fibrils and influence the resulting fibril morphologies (28–30).…”

NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils

“…These IDRs are a substantial fraction of the fibril structure and make up a "fuzzy coat" that surrounds the rigid core (19)(20)(21). The flexible flanking regions in several amyloid proteins have been found to be highly involved in biological interactions, including binding to receptors, chaperones, membranes, or RNA (27). In αS, modifying the "fuzzy coat" through pathologically relevant N-and C-terminal truncations was shown to modulate the aggregation and seeding propensity of αS fibrils and influence the resulting fibril morphologies (28)(29)(30).…”

Tannic Acid Inhibits α-Synuclein Amyloid Fibril Formation via Binding to the Monomer N-terminal Domain

“…The N-terminus of aS has recently been found to mediate the interaction between the IDP monomers and the disordered regions of the fibril that initiates the amyloid seeding process [46,47]. The interaction with the disordered regions of amyloid fibrils that make up their "fuzzy" surface is increasingly being identified to be important in more and more amyloid systems [48]. The N-terminal domain has been identified to play a critical role at the start of aS aggregation [15,49], including the identification of a sequence of 7 residues (36-GVLYVGS-42) that was found to play a critical role in the ability of monomeric aS to aggregate [50].…”