β-Barrels and Amyloids: Structural Transitions, Biological Functions, and Pathogenesis

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.

RopB protein of Rhizobium leguminosarum bv. viciae adopts amyloid state during symbiotic interactions with pea (Pisum sativum L.)

“…Thus, an increase in the RopB production is associated with free-living cellto bacteroid transition but RopB amyloids form at different stages of bacteroid development suggesting their functional role in this process. These observations are in line with other studies demonstrating the amyloidogenic properties of different b-barrel proteins (Sulatskaya et al, 2021). Another b-barrel protein whose detergent-resistant aggregates are detected in the root nodules is vicilin, a seed storage protein of P. sativum L., that contains two ancient cupin b-barrel domains (Bäumlein et al, 1995;Shutov et al, 1995).…”

Digestion Resistance of Soybean 7S Protein and Its Implications for Reinforcing the Gastric Mucus Barrier

“…Soybean 7S protein is a heterogenic trimer, and all three α, α′, and β subunits share the common core region with conserved bi-cupin structures that can adopt the β-barrel conformation. 36 In recent years, accumulated studies have found that many β-barrel proteins form amyloids in vivo for interspecies interactions and nutrient storage 24 for which the native pea vicilin is the amyloid state was also discovered. 23 Therefore, it is more likely that soybean 7S protein contains amyloid aggregates, and pepsin digestion might further facilitate amyloid aggregation.…”

“…23 Vicilin contains conserved β-barrel structures that could be easily self-assembled into amyloid aggregates or fibrils in vivo and in vitro. 24 They also demonstrated that the garden pea amyloid aggregates exhibited digestion resistance to GI enzyme proteolysis and even tolerance to detergent treatment, which depended on the aggregation state. 23 The accumulation of storage protein in amyloid aggregates during seed maturation may be critical for plant seeds to endure extreme conditions (e.g., desiccation and freezing) for long-term survival since these structures are thermodynamically stable, resistant to protease hydrolysis, and thus exhibit poor digestibility to predator insects and animals.…”

“…More recently, Nizhnikov and co-workers discovered that vicilin, the major storage 7S protein (∼47 kDa) in garden pea (Pisum sativum L.) seeds, accumulated in the form of amyloid aggregates during seed maturation . Vicilin contains conserved β-barrel structures that could be easily self-assembled into amyloid aggregates or fibrils in vivo and in vitro . They also demonstrated that the garden pea amyloid aggregates exhibited digestion resistance to GI enzyme proteolysis and even tolerance to detergent treatment, which depended on the aggregation state .…”

The amyloid concentric β‐barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils

“…These results support our proposal that Aβ42 channels contain β-barrels resembling those we proposed for oligomers and APFs. (6) The hypothesis that numerous amyloid oligomers have β-barrel structures and evidence that various β-barrel proteins can form amyloid structures has gained popularity (see Sulatskaya et al 44 for a recent review).…”