Identifying relationships between function, amino acid sequence and protein structure represents a major challenge. In this study we propose a bioinformatics approach that identifies functional keywords in the Swiss-Prot database that correlate with intrinsic disorder. A statistical evaluation is employed to rank the significance of these correlations. Protein sequence data redundancy and the relationship between protein length and protein structure were taken into consideration to ensure the quality of the statistical inferences. Over 200,000 proteins from Swiss-Prot database were analyzed using this approach. The predictions of intrinsic disorder were carried out using PONDR VL3E predictor of long disordered regions that achieves an accuracy of above 86%. Overall, out of the 710 Swiss-Prot functional keywords that were each associated with at least 20 proteins, 238 were found to be strongly positively correlated with predicted long intrinsically disordered regions, whereas 302 were strongly negatively correlated with such regions. The remaining 170 keywords were ambiguous without strong positive or negative correlation with the disorder predictions. These functions cover a large variety of biological activities and imply that disordered regions are characterized by a wide functional repertoire. Our results agree well with literature findings, as we were able to find at least one illustrative example of functional disorder or order shown experimentally for the vast majority of keywords showing the strongest positive or negative correlation with intrinsic disorder. This work opens a series of three papers, which enriches the current view of protein structure-function relationships, especially with regards to functionalities of intrinsically disordered proteins and provides researchers with a novel tool that could be used to improve the understanding of the relationships between protein structure and function. The first paper of the series describes our statistical approach, outlines the major findings and provides illustrative examples of biological processes and functions positively and negatively correlated with intrinsic disorder.

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Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions.

A potent and structurally novel antimicrobial peptide was isolated and characterized from the stomach tissue of Bufo bufo gargarizans, an Asian toad. The 39-amino acid peptide, named buforin I, was purified to homogeneity by heparin-affinity column and reverse-phase HPLC. The amino acid sequence of buforin I was identical in 37 of 39 amino-terminal residues of Xenopus histone H2A. The buforin I showed strong antimicrobial activities in vitro against a broad-spectrum of microorganisms and was found to be more potent than magainin 2. In addition, a 21-amino acid peptide, named buforin II, which was derived from buforin I, showed more potent antimicrobial activities than buforin I.

Isolation and characterization of a novel antimicrobial peptide from Bufo bufo gargarizans = 한국산 두꺼비로부터 새로운 항균 펩타이드 분리와 그 특성 연구

The chemistry and biological activities of peptides from amphibian skin secretions.

Host-defence peptides from the glandular secretions of amphibians: structure and activity

Cationic peptides that adopt an amphipathic α-helical conformation in a membrane-mimetic environment are synthesized in the skins of many frog species. These peptides often display cytolytic activities against bacteria and fungi consistent with the idea that they play a role in the host’s system of defense against pathogenic microorganisms, but their importance in the survival strategy of the animal is not clearly understood. Despite the common misconception that antimicrobial peptides are synthesized in the skins of all anurans, the species distribution is sporadic, suggesting that their production may confer some evolutionary advantage to the organism but is not necessary for survival. The low potency of many frog skin antimicrobial peptides is consistent with the hypothesis that cutaneous symbiotic bacteria may provide the major system of defense against pathogenic microorganisms in the environment with antimicrobial peptides assuming a supplementary role in some species.

Structural diversity and species distribution of host-defense peptides in frog skin secretions

The NMR-derived solution structure of a new cationic antimicrobial peptide from the skin secretion of the anuran Hyla punctata.

The present study reports the structural characteristics, the biological activities, and preliminary clinical investigations of three synthetic members of the dermaseptin family of antimicrobial peptides. The three peptides showed similar tendencies to form α-helical structures in non-polar media. The antimicrobial activity towards bacteria and fungi was determined in the micromolar concentration and the peptides did not influenced peritoneal cells viability. One of the peptides was intravenously administered in mice at concentrations similar to those of antibiotics employed in bacterial/fungal infections and it did not cause any detectable changes in cells and tissues.

Antônio L. T. Araújo

Papers

The NMR-derived solution structure of a new cationic antimicrobial peptide from the skin secretion of the anuran Hyla punctata.

Dermaseptins from Phyllomedusa oreades and Phyllomedusa distincta: Secondary structure, antimicrobial activity, and mammalian cell toxicity.