Amyloidogenic Peptides: New Class of Antimicrobial Peptides with the Novel Mechanism of Activity.

Antibiotic-resistant bacteria are recognized as one of the leading causes of death in the world. We proposed and successfully tested peptides with a new mechanism of antimicrobial action "protein silencing" based on directed co-aggregation. The amyloidogenic antimicrobial peptide (AAMP) interacts with the target protein of model or pathogenic bacteria and forms aggregates, thereby knocking out the protein from its working condition. In this review, we consider antimicrobial effects of the designed peptides on two model organisms, E. coli and T. thermophilus, and two pathogenic organisms, P. aeruginosa and S. aureus. We compare the amino acid composition of proteomes and especially S1 ribosomal proteins. Since this protein is inherent only in bacterial cells, it is a good target for studying the process of co-aggregation. This review presents a bioinformatics analysis of these proteins. We sum up all the peptides predicted as amyloidogenic by several programs and synthesized by us. For the four organisms we studied, we show how amyloidogenicity correlates with antibacterial properties. Let us especially dwell on peptides that have demonstrated themselves as AMPs for two pathogenic organisms that cause dangerous hospital infections, and in which the minimal inhibitory concentration (MIC) turned out to be comparable to the MIC of gentamicin sulfate. All this makes our study encouraging for the further development of AAMP. The hybrid peptides may thus provide a starting point for the antibacterial application of amyloidogenic peptides.

Amyloidogenic Propensities of Ribosomal S1 Proteins: Bioinformatics Screening and Experimental Checking.

Structural S1 domains belong to the superfamily of oligosaccharide/oligonucleotide-binding fold domains, which are highly conserved from prokaryotes to higher eukaryotes and able to function in RNA binding. An important feature of this family is the presence of several copies of the structural domain, the number of which is determined in a strictly limited range from one to six. Despite the strong tendency for the aggregation of several amyloidogenic regions in the family of the ribosomal S1 proteins, their fibril formation process is still poorly understood. Here, we combined computational and experimental approaches for studying some features of the amyloidogenic regions in this protein family. The FoldAmyloid, Waltz, PASTA 2.0 and Aggrescan programs were used to assess the amyloidogenic propensities in the ribosomal S1 proteins and to identify such regions in various structural domains. The thioflavin T fluorescence assay and electron microscopy were used to check the chosen amyloidogenic peptides' ability to form fibrils. The bioinformatics tools were used to study the amyloidogenic propensities in 1331 ribosomal S1 proteins. We found that amyloidogenicity decreases with increasing sizes of proteins. Inside one domain, the amyloidogenicity is higher in the terminal parts. We selected and synthesized 11 amyloidogenic peptides from the Escherichia coli and Thermus thermophilus ribosomal S1 proteins and checked their ability to form amyloids using the thioflavin T fluorescence assay and electron microscopy. All 11 amyloidogenic peptides form amyloid-like fibrils. The described specific amyloidogenic regions are actually responsible for the fibrillogenesis process and may be potential targets for modulating the amyloid properties of bacterial ribosomal S1 proteins.

Variation in base composition, structure-function relationships, and origins of structural repetition in bacterial rpsA gene.

Protein domain repeats are known to arise due to tandem duplications of internal genes. However, the understanding of the underlying mechanisms of this process is incomplete. The goal of this work was to investigate the mechanism of occurrence of repeat expansion based on studying the sequences of 1324 rpsA genes of bacterial S1 ribosomal proteins containing different numbers of S1 structural domains. The rpsA gene encodes ribosomal S1 protein, which is essential for cell viability as it interacts with both mRNA and proteins. Gene ontology (GO) analysis of S1 domains in ribosomal S1 proteins revealed that bacterial protein sequences in S1 mainly have 3 types of molecular functions: RNA binding activity, nucleic acid activity, and ribosome structural component. Our results show that the maximum value of rpsA gene identity for full-length proteins was found for S1 proteins containing six structural domains (58%). Analysis of consensus sequences showed that parts of the rpsA gene encoding separate S1 domains have no a strictly repetitive structure between groups containing different numbers of S1 domains. At the same time, gene regions encoding some conserved residues that form the RNA-binding site remain conserved. The detected phylogenetic similarity suggests that the proposed fold of the rpsA translation initiation region of Escherichia coli has functional value and is important for translational control of rpsA gene expression in other bacterial phyla, but not only in gamma Proteobacteria.

Diversity and features of proteins with structural repeats.

The review provides information on proteins with structural repeats, including their classification, characteristics, functions, and relevance in disease development. It explores methods for identifying structural repeats and specialized databases. The review also highlights the potential use of repeat proteins as drug design scaffolds and discusses their evolutionary mechanisms.