Abstract
The development of many severe human diseases is associated with the formation of amyloid fibrils. Most of the available information on the process of amyloid formation has been obtained from studies of small proteins and peptides, wherein the features of complex proteins’ aggregation remain insufficiently investigated. Our work aimed to research the amyloid aggregation of a large model protein, bovine carbonic anhydrase B (BCAB). It has previously been demonstrated that, when exposed to an acidic pH and elevated temperature, this protein forms amyloid fibrils. Here, we show that, under these conditions and before amyloid formation, BCAB undergoes fragmentation by acid hydrolysis to give free individual peptides and associated peptides. Fragments in associates contain a pronounced secondary structure and act as the main precursor of amyloid fibrils, wherein free peptides adopt mostly unstructured conformation and form predominantly irregular globular aggregates. Reduced acidity decreases the extent of acid hydrolysis, causing BCAB to form amorphous aggregates lacking the thioflavin T binding β-structure. The presented results provide new information on BCAB amyloid formation and show the importance of protein integrity control when working even in mildly acidic conditions.
Highlights
Protein misfolding and the formation of amyloid aggregates are causes of severe diseases which are currently considered incurable
Our work aimed to investigate the aggregation of a large model protein, bovine carbonic anhydrase B (BCAB), which serves as a convenient model with a well-described folding [29,30,31]
We show for the first time that, under amyloid formation conditions, BCAB is susceptible to acid hydrolysis
Summary
Protein misfolding and the formation of amyloid aggregates are causes of severe diseases which are currently considered incurable. Based on the data obtained, it was concluded that forming amyloid fibrils is specific, for disease-associated proteins. Biomolecules 2021, 11, 1608 common property of all polypeptide chains [15] These results led to an intensive study of amyloid aggregation using model proteins as examples [17,18,19]. Based on the experimental data on the aggregation of BCAB and the peptide corresponding to amino acid residues 201–227, a conclusion on differences in amyloid formation by the full-length protein and its fragment has been drawn [36]. Our results on the amyloid formation accompanied by the fragmentation of the precursor protein can help us to understand the mechanism of in vivo aggregation of proteolysis-yielded peptides
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