Pore-Forming Proteins Share Structural and Functional Homology with Amyloid Oligomers

Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
NeuroMolecular Medicine (Impact Factor: 3.68). 02/2007; 9(3):270-5. DOI: 10.1007/s12017-007-0003-6
Source: PubMed


Degenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases are believed to be causally related to the accumulation of amyloid oligomers that exhibit a common structure and may be toxic by a common mechanism involving permeabilization of membranes. We discovered that amyloid oligomers and the pore-forming bacterial toxin, alpha-hemolysin (alpha HL), as well as human perforin from cytotoxic T lymphocytes, share a structural and functional homology at the level of their common reactivity with a conformation-dependent antibody that is specific for amyloid oligomers, A11. The alpha HL oligomeric pores and partially folded alpha HL protomer, but not the monomer alpha HL precursor reacts with A11 antibody. A11 antibody inhibits the hemolytic activity of alpha HL, indicating that the structural homology is functionally significant. Perforin oligomers were also recognized by A11. Amyloidogenic properties of alpha HL and perforin were confirmed spectroscopically and morphologically. These results indicate that pore forming proteins (PFP) and amyloid oligomers share structural homology and suggest that PFPs and amyloid oligomers share the same mechanism of membrane permeabilization.

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    • "Our findings support previous reports demonstrating that amyloid assemblies interact with cell membranes, causing ion flux through artificial and cellular lipid membranes52. Furthermore, Glabe and coworkers have shown that amyloid oligomers share structural and functional homology with pore forming proteins like alpha-hemolysin from the bacterium Staphylococcus aureus, as well as human perforin from cytotoxic T lymphocytes53. "
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    Scientific Reports 03/2014; 4:4267. DOI:10.1038/srep04267 · 5.58 Impact Factor
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    • "Our recent study has shown that the complement activation contributes to muscle pathology in dysferlinopathy [22]. Moreover, the beta-amyloid can also form ring-shaped structures reminiscent of bacterial pore-forming toxins (PFTs) [23], which have membrane-perforating activity [24]. Interestingly, increased sarcolemmal and interstitial amyloid deposits were observed in dysferlinopathy patient muscles, and mutant dysferlin was found to be present in the amyloid deposits [25]. "
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    BioMed Research International 09/2011; 2011:235216. DOI:10.1155/2011/235216 · 2.71 Impact Factor
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    • "Therefore, a permeabilization mechanism involving pore formation by the HMW A␤ 42 aggregates cannot be excluded a priori. It is relevant to point out here that poreforming proteins, like the bacterial toxin ␣-hemolysin and human perforin, share structural homology with amyloid oligomers suggesting a common mechanism of membrane permeabilization [64]. The ability of small molecule compounds and black tea extract to protect phospholipid membranes from disruption by A␤ aggregates was tested using our permeabilization assay. "
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