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Supramolecular Organization As a Factor of Ribonuclease Cytotoxicity.

ABSTRACT: One of the approaches used to eliminate tumor cells is directed destruction/modification of their RNA molecules. In this regard, ribonucleases (RNases) possess a therapeutic potential that remains largely unexplored. It is believed that the biological effects of secreted RNases, namely their antitumor and antiviral properties, derive from their catalytic activity. However, a number of recent studies have challenged the notion that the activity of RNases in the manifestation of selective cytotoxicity towards cancer cells is exclusively an enzymatic one. In this review, we have analyzed available data on the cytotoxic effects of secreted RNases, which are not associated with their catalytic activity, and we have provided evidence that the most important factor in the selective apoptosis-inducing action of RNases is the structural organization of these enzymes, which determines how they interact with cell components. The new idea on the preponderant role of non-catalytic interactions between RNases and cancer cells in the manifestation of selective cytotoxicity will contribute to the development of antitumor RNase-based drugs.

SUBMITTER: Dudkina EV

PROVIDER: S-EPMC7604891 | biostudies-literature | 2020 Jul-Sep

REPOSITORIES: biostudies-literature

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Supramolecular Organization As a Factor of Ribonuclease Cytotoxicity.

Dudkina E V EV Ulyanova V V VV Ilinskaya O N ON

Acta naturae 20200701 3

One of the approaches used to eliminate tumor cells is directed destruction/modification of their RNA molecules. In this regard, ribonucleases (RNases) possess a therapeutic potential that remains largely unexplored. It is believed that the biological effects of secreted RNases, namely their antitumor and antiviral properties, derive from their catalytic activity. However, a number of recent studies have challenged the notion that the activity of RNases in the manifestation of selective cytotoxi ...[more]

PMID: 33173594

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Project description:The unique physiochemical properties and multiscale organization of layered materials draw the attention of researchers across a wide range of scientific disciplines. Layered structures are commonly found in diverse biological systems where they fulfill various functions. A prominent example of layered biological materials is the organization of proteins and polypeptides into the archetypal aggregated amyloidal structures. While the organization of proteins into amyloid structures was initially associated with various degenerative disorders, it was later revealed that proteins not related to any disease could also form identical layered assemblies. Thus, it appears that the ability of peptides and proteins to produce amyloid-like aggregates represents a generic property of polyamides to assemble into higher order fibrillar structures. In the aggregated state, the peptide backbone forms ?-sheet structures which are further organized into layered arrangements. We have recently extended the identified amyloidogenic building blocks to include not only peptides or proteins, but also single amino acids and other metabolites. High resolution spectroscopy and crystallography analyses confirm the clear potential of amino acids and other metabolites to form layered amyloid-like aggregates showing biophysical and biochemical properties similar to protein amyloids. Therefore, the generic propensity of peptides and proteins backbones to assemble into layered organizations may emanate from their basic building block, the amino acid. In this Account, we aim to introduce the concept of supramolecular ?-sheet organization of single amino acids and to present an analysis of their layered-structure organization based on single crystal structures. We demonstrate that, despite the different side-chains that considerably vary in their chemical properties, all coded amino acids display a layer-like assembly stabilized by ?-amine to ?-carboxyl H-bonds, resembling supramolecular ?-sheet structures, while the side-chains determine the higher order organization of the layers. Our work presents the first analysis of the ?-sheet propensity of single amino acids in their unbound form, indicating an evolutionary predisposition. We classify the amino acids ?-sheet propensity on the basis of the interlayer separation distance in the crystal packing, which correlates well with previously reported classifications based on various criteria, such as hydrophobicity, steric bulkiness, and folding. In addition, we demonstrate that the relative direction of ?-amine to ?-carboxyl H-bonding pattern provides critical insights regarding the stabilization of parallel versus antiparallel ?-sheet structures by the various amino acids. Taken together, our analysis of amino acid crystals provides substantial information regarding protein folding and dynamics and could serve as basic rules set for the design of potential building blocks for molecular self-assembly to produce functional materials of tunable properties, an important objective of bottom-up nanotechnology.

Dataset Information

Supramolecular Organization As a Factor of Ribonuclease Cytotoxicity.

Publications

Supramolecular Organization As a Factor of Ribonuclease Cytotoxicity.

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