Caspase 8 mediated apoptotic cell death induced by beta-sheet forming polyalanine peptides.
Expansion of a polyalanine stretch from 10 to 12-17 residues in the N-terminus of the protein PABP2 has been implicated in the genetically acquired disease oculopharyngeal muscular dystrophy, characterized by nuclear protein deposits. Here we report a correlation between the structural properties and cell toxicity of two peptides mimicking the N-terminal domain of PABP2: one containing seven and the other 11 uninterrupted alanine residues. Consistent with earlier observations, the longer peptide (11-ala) was found to adopt beta-sheet structure while the shorter one (7-ala) formed alpha-helix over a wide range of concentrations ( approximately 20-500 microM). We observed that treatment with 11-ala resulted in significantly enhanced death of Chinese hamster V79 cells, compared to the effect of treatment with 7-ala, via the cytochrome c mediated apoptotic pathway. Increases in caspase 8 and caspase 3 activity were also observed in human cells (K562) treated with 11-ala. These results indicate that the toxicity of pathogenic peptides is directly linked to their beta-sheet structure and also support recent observations that small oligomeric species of peptides and proteins are the key toxic elements in causing protein aggregation diseases.
Giri
Kalyan
K
Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Calcutta 700 064, India.
Ghosh
Utpal
U
Bhattacharyya
Nitai P
NP
Basak
Soumen
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002942:Circular Dichroism; D006224:Cricetinae; D003412:Cricetulus; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D008297:Male; D008856:Microscopy, Fluorescence; D009707:Nucleosomes / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000633:toxicity*; D039103:Poly(A)-Binding Protein II / Q000737:chemistry*; D017433:Protein Structure, Secondary
D009707:Nucleosomes; D009842:Oligopeptides; D039103:Poly(A)-Binding Protein II; D045304:Cytochromes c; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases