Pore-Forming Proteins Share Structural and Functional Homology with Amyloid Oligomers
ABSTRACT 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.
- SourceAvailable from: Anat Frydman-Marom
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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. "
ABSTRACT: Soluble oligomeric assemblies of amyloidal proteins appear to act as major pathological agents in several degenerative disorders. Isolation and characterization of these oligomers is a pivotal step towards determination of their pathological relevance. Here we describe the isolation of Type 2 diabetes-associated islet amyloid polypeptide soluble cytotoxic oligomers; these oligomers induced apoptosis in cultured pancreatic cells, permeated model lipid vesicles and interacted with cell membranes following complete internalization. Moreover, antibodies which specifically recognized these assemblies, but not monomers or amyloid fibrils, were exclusively identified in diabetic patients and were shown to neutralize the apoptotic effect induced by these oligomers. Our findings support the notion that human IAPP peptide can form highly toxic oligomers. The presence of antibodies identified in the serum of diabetic patients confirms the pathological relevance of the oligomers. In addition, the newly identified structural epitopes may also provide new mechanistic insights and a molecular target for future therapy.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 . Moreover, the beta-amyloid can also form ring-shaped structures reminiscent of bacterial pore-forming toxins (PFTs) , which have membrane-perforating activity . 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 . "
ABSTRACT: Dysferlin plays an important role in repairing membrane damage elicited by laser irradiation, and dysferlin deficiency causes muscular dystrophy and associated cardiomyopathy. Proteins such as perforin, complement component C9, and bacteria-derived cytolysins, as well as the natural detergent saponin, can form large pores on the cell membrane via complexation with cholesterol. However, it is not clear whether dysferlin plays a role in repairing membrane damage induced by pore-forming reagents. In this study, we observed that dysferlin-deficient muscles recovered the tetanic force production to the same extent as their WT counterparts following a 5-min saponin exposure (50 μg/mL). Interestingly, the slow soleus muscles recovered significantly better than the fast extensor digitorum longus (EDL) muscles. Our data suggest that dysferlin is unlikely involved in repairing saponin-induced membrane damage and that the slow muscle is more efficient than the fast muscle in repairing such damage.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 . 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. "
ABSTRACT: Amyloid-β (Aβ) aggregation is a recognized key process in the pathogenesis of Alzheimer's disease (AD). Misfolded Aβ peptides self-assemble into higher-order oligomers that compromise membrane integrity, leading to synaptic degeneration and neuronal cell death. The main aim of this study was to explore whether small-molecule compounds and black tea extract can protect phospholipid membranes from disruption by Aβ aggregates. We first established a robust protocol for aggregating Aβ₄₂ peptides into a range of oligomers that efficiently permeabilized small unilamellar liposomes. Next, 15 natural plant polyphenolic compounds, 8 N'-benzylidene-benzohydrazide (NBB) compounds and black tea extract were assessed for their ability to antagonize liposome permeabilization by the Aβ₄₂ oligomers. Our data indicates that black tea extract, the flavones apigenin and baicalein, and the stilbene nordihydroguaiaretic acid (NDGA) are indeed potent inhibitors. Taking into consideration the results of all the small-molecule polyphenols and NBB compounds, it can be proposed that a dihydroxyphenyl ring structure, alone or as part of a flavone scaffold, is particularly effective for protection against membrane damage by the Aβ₄₂ oligomers. Given the critical role of membrane perforation in the neurodegenerative cascade, these conclusions may guide the design and development of novel therapeutic drugs in AD.Journal of Alzheimer's disease: JAD 09/2011; 27(4):767-79. DOI:10.3233/JAD-2011-111061 · 4.15 Impact Factor