Caspase 8 mediated apoptotic cell death induced by β‐sheet forming polyalanine peptides
- 14 November 2003
- journal article
- Published by Wiley in FEBS Letters
- Vol. 555 (2) , 380-384
- https://doi.org/10.1016/s0014-5793(03)01294-8
Abstract
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.Keywords
This publication has 27 references indexed in Scilit:
- Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disordersNature, 2003
- Polyglutamine PathogenesisNeuron, 2002
- Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseasesNature, 2002
- Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner HippiNature Cell Biology, 2002
- Extended polyglutamine selectively interacts with caspase-8 and -10 in nuclear aggregatesCell Death & Differentiation, 2001
- Trinucleotide Repeats: Mechanisms and PathophysiologyAnnual Review of Genomics and Human Genetics, 2000
- Aggregates from mutant and wild‐type α‐synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of β‐sheet and amyloid‐like filamentsFEBS Letters, 1998
- Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophyNature Genetics, 1998
- Altered Growth and Branching Patterns in Synpolydactyly Caused by Mutations in HOXD13Science, 1996
- Presence of inclusion body myositis‐like filaments in oculopharyngeal muscular dystrophy. Ultrastructural study of 10 casesNeuropathology and Applied Neurobiology, 1990