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An additional mechanism of ribosome-inactivating protein cytotoxicity: degradation of extrachromosomal DNA.

ABSTRACT: Inhibition of protein synthesis by cleavage of the N-glycosidic bond of a specific adenine of 28 S rRNA has been accepted as the mechanism by which plant ribosome-inactivating proteins (RIPs) cause cytotoxicity. The cytotoxic action of gelonin on Plasmodium falciparum malaria parasites appears to occur by a different mechanism. Parasite intoxication, which is manifested by mitochondrial dysfunction and lack of nucleic acid synthesis in the erythrocytic cycle following exposure to the toxin, is caused by the elimination of the parasite 6 kb extrachromosomal (mitochondrial) DNA. This is the first report which demonstrates that the DNA-damaging activities of RIPs observed in vitro can contribute to their cytotoxicity.

SUBMITTER: Nicolas E

PROVIDER: S-EPMC1218809 | biostudies-other | 1997 Oct

REPOSITORIES: biostudies-other

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Project description:Pokeweed antiviral protein (PAP) belongs to the family of type I ribosome‑inactivating proteins (RIPs): Ribotoxins, which function by depurinating the sarcin‑ricin loop of ribosomal RNA. In addition to its antibacterial and antifungal properties, PAP has shown promise in antiviral and targeted tumor therapy owing to its ability to depurinate viral RNA and eukaryotic rRNA. Several PAP genes are differentially expressed across pokeweed tissues, with natively isolated seed forms of PAP exhibiting the greatest cytotoxicity. To help elucidate the molecular basis of increased cytotoxicity of PAP isoenzymes from seeds, the present study used protein sequencing, mass spectroscopy and X-ray crystallography to determine the complete covalent structure and 1.7 Å X‑ray crystal structure of PAP‑S1aci isolated from seeds of Asian pokeweed (Phytolacca acinosa). PAP‑S1aci shares ~95% sequence identity with PAP‑S1 from P. americana and contains the signature catalytic residues of the RIP superfamily, corresponding to Tyr72, Tyr122, Glu175 and Arg178 in PAP‑S1aci. A rare proline substitution (Pro174) was identified in the active site of PAP‑S1aci, which has no effect on catalytic Glu175 positioning or overall active‑site topology, yet appears to come at the expense of strained main‑chain geometry at the pre‑proline residue Val173. Notably, a rare type of N‑glycosylation was detected consisting of N‑acetyl‑D‑glucosamine monosaccharide residues linked to Asn10, Asn44 and Asn255 of PAP‑S1aci. Of note, our modeling studies suggested that the ribosome depurination activity of seed PAPs would be adversely affected by the N‑glycosylation of Asn44 and Asn255 with larger and more typical oligosaccharide chains, as they would shield the rRNA‑binding sites on the protein. These results, coupled with evidence gathered from the literature, suggest that this type of minimal N‑glycosylation in seed PAPs and other type I seed RIPs may serve to enhance cytotoxicity by exploiting receptor‑mediated uptake pathways of seed predators while preserving ribosome affinity and rRNA recognition.

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An additional mechanism of ribosome-inactivating protein cytotoxicity: degradation of extrachromosomal DNA.

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