Abstract
The idea that amyloid fibrils and other types of protein aggregates are toxic for cells has been challenged by the discovery of a variety of functional aggregates. However, an identification of crucial differences between pathological and functional aggregation remains to be explored. Functional protein aggregation is often reversible by nature in order to respond properly to changing physiological conditions of the cell. In addition, increasing evidence indicates that fast fibril growth is a feature of functional amyloids, providing protection against the long-term existence of potentially toxic oligomeric intermediates. It is becoming clear that functional protein aggregation is a complexly organized process that can be mediated by a multitude of biomolecular factors. In this overview, we discuss the roles of diverse biomolecules, such as lipids/membranes, glycosaminoglycans, nucleic acids and metal ions, in regulating functional protein aggregation. Our studies on the protein GAPR-1 revealed that several of these factors influence the amyloidogenic properties of this protein. These observations suggest that GAPR-1, as well as the cysteine-rich secretory proteins, antigen 5 and pathogenesis-related proteins group 1 (CAP) superfamily of proteins that it belongs to, require the assembly into an amyloid state to exert several of their functions. A better understanding of functional aggregate formation may also help in the prevention and treatment of amyloid-related diseases.
Highlights
Introduction to Protein AggregatesTwo Sides of a CoinProtein aggregation is a biochemical process in which proteins accumulate or clump together to form aggregates and/or membrane-less inclusions, either intracellularly or extracellularly [1,2,3,4]
Amyloid formation is a distinct type of protein aggregation in which soluble proteins assemble into highly ordered, biochemically stable fibrils with a cross-β structure [3,5,6]
The expression and degradation of the precursors of functional amyloid fibrils are tightly controlled because high levels of an amyloidogenic precursor could initiate unwanted amyloid aggregation [32]
Summary
Protein aggregation is a biochemical process in which proteins accumulate or clump together to form aggregates and/or membrane-less inclusions, either intracellularly or extracellularly [1,2,3,4]. Amyloid formation is a distinct type of protein aggregation in which soluble proteins assemble into highly ordered, biochemically stable fibrils with a cross-β structure [3,5,6]. The structure of amyloids enables their use as scaffolds for biochemical activities and the compact nature of aggregates makes them highly suitable as sites for protein storage. Functional protein aggregates appeared crucial for a variety of biological activities, including the storage of peptide hormones [7,8], reproduction and fertilization [9,10,11], pigmentation [12], necroptosis [13], antimicrobial responses [14], adaptation to. Althltohuougghhfufunncctitoionnaallaaggggrreeggates are noott lleetthhaallttoocceellsls, ,ppootetenntitailalyllytotxoixciicnitnertemremdeiadtieastes dodeoxiesxtisdtudruinrigntghtehieriarsassesmembblyly[3[322].].FFoorreexxaammppllee,, tthhee iinntteerrmmeeddiaiateteoolilgigoommeresrsofopf ipgimgmenetnctelcle-sllp-sepcieficcific prep-rme-emlaenloansoomsoaml palropterointe(iPnM(PEML)EaLn)daOnrdb2O, arbk2e,yaprkoetyeinprfootrelionnfgo-rtelromngm-teemrmorymfeomrmoraytiofonrimnaDtiroonsopinhila, areDtrooxsoicp,hwilah, earreeatsoxthice, wmhaetrueraes athmeymloaitdursetaatmeyolfotidhesstaeteproofttehiensseipsrfoutenicntsioisnfauln[3ct3i,o3n4a]l. [I3n3,o3r4d].eIrntooradveroid toxtiociatvy,ofiduntoctxiiocnitayl, afugngcrteigonatailoangmgruegstattihoenremfourset tbheertiegfohrtelybreetgiguhlatltyedre[g3u2l]a. ted [32]
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