Abstract
Insoluble protein aggregates with fibrillar morphology called amyloids and β-barrel proteins both share a β-sheet-rich structure. Correctly folded β-barrel proteins can not only function in monomeric (dimeric) form, but also tend to interact with one another—followed, in several cases, by formation of higher order oligomers or even aggregates. In recent years, findings proving that β-barrel proteins can adopt cross-β amyloid folds have emerged. Different β-barrel proteins were shown to form amyloid fibrils in vitro. The formation of functional amyloids in vivo by β-barrel proteins for which the amyloid state is native was also discovered. In particular, several prokaryotic and eukaryotic proteins with β-barrel domains were demonstrated to form amyloids in vivo, where they participate in interspecies interactions and nutrient storage, respectively. According to recent observations, despite the variety of primary structures of amyloid-forming proteins, most of them can adopt a conformational state with the β-barrel topology. This state can be intermediate on the pathway of fibrillogenesis (“on-pathway state”), or can be formed as a result of an alternative assembly of partially unfolded monomers (“off-pathway state”). The β-barrel oligomers formed by amyloid proteins possess toxicity, and are likely to be involved in the development of amyloidoses, thus representing promising targets for potential therapy of these incurable diseases. Considering rapidly growing discoveries of the amyloid-forming β-barrels, we may suggest that their real number and diversity of functions are significantly higher than identified to date, and represent only “the tip of the iceberg”. Here, we summarize the data on the amyloid-forming β-barrel proteins, their physicochemical properties, and their biological functions, and discuss probable means and consequences of the amyloidogenesis of these proteins, along with structural relationships between these two widespread types of β-folds.
Highlights
Amyloids are insoluble fibrillar protein aggregates that are rich in β-sheets and possess a unique spatial structure called “cross-β” [1]
The ability of proteins to form amyloids is determined by the presence of specific aggregation-prone regions in their amino acid sequence. These regions are called amyloidogenic, and can be predicted by different bioinformatic approaches [19]. These regions differ in their structure and amino acid composition, but there are at least two well-defined groups of such regions: (1) Q and/or N-rich, which are typical for infectious amyloids of yeast and several pathological amyloids of mammals [20], and (2) rich in hydrophobic residues, which are found in various pathological and functional amyloids
Unfolded β-barrel proteins in the solutions are prone to aggregation and exhibit high structural polymorphism (Table 2), including both disordered aggregates and amyloid fibrils
Summary
Amyloids are insoluble fibrillar protein aggregates that are rich in β-sheets and possess a unique spatial structure called “cross-β” [1]. The ability of proteins to form amyloids is determined by the presence of specific aggregation-prone regions in their amino acid sequence. These regions are called amyloidogenic, and can be predicted by different bioinformatic approaches [19]. These regions differ in their structure and amino acid composition, but there are at least two well-defined groups of such regions: (1) Q and/or N-rich, which are typical for infectious amyloids of yeast and several pathological amyloids of mammals [20], and (2) rich in hydrophobic residues, which are found in various pathological and functional amyloids. We discuss the functional and pathological roles of these biological processes
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