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Published on: June 28, 2013
Parasporins 1 and 2: Their structure and activity
Toshihiko Akiba1, Shiro Okumura2
1Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Abstract:
Parasporins are novel protein toxins preferentially cytotoxic against human cancer cells. They are obtained from parasporal inclusions of Bacillus thuringiensis and, accordingly, are considered congeners of the insecticidal Cry toxins. Two types of parasporins have been identified: the three-domain Cry toxin type and the β-pore-forming-toxin (β-PFT) type. Crystal structures of representative members of the two types, PS1Aa1 and PS2Aa1, have been determined and compared with those of well-studied toxins. PS1Aa1 has a typical architecture characteristic of the three-domain insecticidal Cry toxins, though it is cleaved into two polypeptides. It has an extra N-terminal segment found only in the inactive form of the Cry toxins and, hence, it is presumed to act through another mechanism as an activator in the apoptotic signaling pathway rather than a pore-forming toxin. PS2Aa1 shows a remarkable structural similarity to the aerolysin-type β-PFTs, which is much greater than expected from its limited sequence identity to those toxins. This strongly suggests that a pore-forming mechanism similar to that of β-PFTs is involved in the action of this type of parasporin. The structural comparison of PS2Aa1 to other aerolysin-type β-PFTs indicates conserved oligomerization and pore-forming structures in domains 2 and 3, and highly diverse putative receptor binding region structures in domain 1, likely accounting for enhanced cancer cell cytotoxicity as compared to normal control cells. The structural implications for the mechanism of action and cellular specificity of both Cry and β-PFT type parasporins will be enhanced by further experimental validation.
Insights
Parasporins, toxins from Bacillus thuringiensis, show selective cancer cell killing. Structural analysis reveals two types: Cry toxins and beta-pore-forming toxins (β-PFTs), suggesting distinct mechanisms for cancer therapy.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Toxicology
Background:
- Parasporins are novel protein toxins derived from Bacillus thuringiensis.
- They exhibit preferential cytotoxicity against human cancer cells.
- Parasporins are classified into two types: three-domain Cry toxin type and β-pore-forming-toxin (β-PFT) type.
Purpose of the Study:
- To elucidate the structural characteristics of two representative parasporins, PS1Aa1 (Cry type) and PS2Aa1 (β-PFT type).
- To compare their structures with known toxins to understand their mechanisms of action and cellular specificity.
- To explore the potential of parasporins as targeted cancer therapeutics.
Main Methods:
- Determination of crystal structures for PS1Aa1 and PS2Aa1.
- Comparative structural analysis with established insecticidal Cry toxins and aerolysin-type β-PFTs.
- Analysis of structural domains related to oligomerization, pore formation, and receptor binding.
Main Results:
- PS1Aa1 shares structural features with three-domain insecticidal Cry toxins but possesses an N-terminal segment suggesting an alternative apoptotic signaling role.
- PS2Aa1 exhibits significant structural similarity to aerolysin-type β-PFTs, indicating a pore-forming mechanism.
- Structural variations in the domain 1 receptor-binding region of PS2Aa1 likely contribute to its enhanced cancer cell specificity.
Conclusions:
- Parasporins employ distinct structural mechanisms, either related to Cry toxins or β-PFTs, for their cytotoxic effects.
- Structural insights support the potential of parasporins as targeted anticancer agents.
- Further experimental validation is required to fully understand the mechanism of action and cellular specificity of both parasporin types.
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