Functional Amyloids Are the Rule Rather Than the Exception in Cellular Biology

Abstract

Amyloids are a class of protein aggregates that have been historically characterized by their relationship with human disease. Indeed, amyloids can be the result of misfolded proteins that self-associate to form insoluble, extracellular plaques in diseased tissue. For the first 150 years of their study, the pathogen-first definition of amyloids was sufficient. However, new observations of amyloids foster an appreciation for non-pathological roles for amyloids in cellular systems. There is now evidence from all domains of life that amyloids can be non-pathogenic and functional, and that their formation can be the result of purposeful and controlled cellular processes. So-called functional amyloids fulfill an assortment of biological functions including acting as structural scaffolds, regulatory mechanisms, and storage mechanisms. The conceptual convergence of amyloids serving a functional role has been repeatedly confirmed by discoveries of additional functional amyloids. With dozens already known, and with the vigorous rate of discovery, the biology of amyloids is robustly represented by non-pathogenic amyloids.

Molecular architecture of the TasA biofilm scaffold in Bacillus subtilis

“…A recurring theme in bacterial biofilms is the abundance of filamentous molecules including polysaccharides [40, 41], proteins [24] and DNA [42] in the ECM [3], which are possibly important for the formation of a phase-separated environment protecting cells within biofilms [43, 44]. Further studies into such mechanisms will be important to understand how the ECM is formed, which is of fundamental importance in comprehending how biofilms are built.…”

“…These unique features explain why previous studies have arrived at different expected subunit arrangements of TasA within the filament. While it is well established that functional amyloids are abundant in bacteria and beyond [24], we propose that other suggested functional amyloids could also exhibit similar characteristics, and that there may be a continuum of fibre-forming proteins - on one end arranged as classical amyloids [25, 37], to amyloid-like fibres displaying features shared with filaments formed from globular proteins on the other end [27].…”

A conserved mechanism regulates reversible amyloids via pH-sensing regions

“…However, an expanding number of amyloids have also been found to exert important physiological roles. Indeed, functional amyloids have been described in bacteria, fungi, plants and mammals, fulfilling a wide variety of tasks including long-term memory formation, stress response, metabolism regulation, hormone storage and melanin production 2 . Interestingly, recent structural studies of functional amyloids highlighted their similarity to pathological aggregates, raising the question of what differentiates functional from toxic aggregates 3 .…”

“… AbstractAmyloids were long viewed as irreversible, pathological aggregates, often associated with neurodegenerative diseases 1 . However, recent insights challenge this view, providing evidence that reversible amyloids can form upon stress conditions and fulfil crucial cellular functions 2 . Yet, the molecular mechanisms regulating functional amyloids and the differences to their pathological counterparts remain poorly understood.…”

Amyloid Proteins in Plant-Associated Microbial Communities

“…All of these biofilm amyloids require unique and intricate pathways with numerous intermediate enzymes and safety stops that keep aggregation under control [Balistreri et al, 2020], as its unintended trigger in the cytoplasm would overwhelm chaperones and lead to cell death [Landreh et al, 2015]. Additionally, there are usually two or more proteins that are directly responsible for amyloid formation: the major subunit protein that makes up most of the fibril's weight but is unable to polymerize on its own, or does so slowly, and the minor subunit that acts as a nucleator.…”