Caspase 8 mediated apoptotic cell death induced by β‐sheet forming polyalanine peptides

FEBS Letters

Bhattacharyya, Nitai P¹  Giri, Kalyan²  Ghosh, Utpal¹  Basak, Soumen² 

[1] Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Calcutta 700 064, India;Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Calcutta 700 064, India

关键词: Aggregation;    Oculopharyngeal muscular dystrophy;    Polyalanine;    Circular dichroism;    Beta-sheet;    Apoptosis;   

DOI  :  10.1016/S0014-5793(03)01294-8

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 β-sheet structure while the shorter one (7-ala) formed α-helix over a wide range of concentrations (∼20–500 μM). 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 β-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.

【 授权许可】

Unknown