A causative link between the structure of aberrant protein oligomers and their toxicity

Department of Biochemical Sciences, University of Florence, Florence, Italy.
Nature Chemical Biology (Impact Factor: 13.22). 02/2010; 6(2):140-7. DOI: 10.1038/nchembio.283
Source: PubMed

ABSTRACT The aberrant assembly of peptides and proteins into fibrillar aggregates proceeds through oligomeric intermediates that are thought to be the primary pathogenic species in many protein deposition diseases. We describe two types of oligomers formed by the HypF-N protein that are morphologically and tinctorially similar, as detected with atomic force microscopy and thioflavin T assays, though one is benign when added to cell cultures whereas the other is toxic. Structural investigation at a residue-specific level using site-directed labeling with pyrene indicated differences in the packing of the hydrophobic interactions between adjacent protein molecules in the oligomers. The lower degree of hydrophobic packing was found to correlate with a higher ability to penetrate the cell membrane and cause an influx of Ca(2+) ions. Our findings suggest that structural flexibility and hydrophobic exposure are primary determinants of the ability of oligomeric assemblies to cause cellular dysfunction and its consequences, such as neurodegeneration.

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Available from: Silvia Campioni, Sep 08, 2014
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    • "Although recent advances in structural methods have enabled the conformational properties of rarely populated, partially folded monomers of aggregation-prone proteins to be determined (Eichner et al., 2011; Jahn et al., 2006; Neudecker et al., 2012), the nature of the first protein-protein interactions that initiate amyloid formation remains unclear. Early in assembly an array of biomolecular interactions arise, some of which may be productive for amyloid formation, whereas others may be unproductive, with the potential to inhibit or retard amyloid assembly (Campioni et al., 2010; Cremades et al., 2012). The course of amyloid assembly thus may depend on the stability and lifetime of the productive interactions versus their unproductive counterparts . "
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    ABSTRACT: In the early stages of amyloid formation, heterogeneous populations of oligomeric species are generated, the affinity, specificity, and nature of which may promote, inhibit, or define the course of assembly. Despite the importance of the intermolecular interactions that initiate amyloid assembly, our understanding of these events remains poor. Here, using amyloidogenic and nonamyloidogenic variants of β2-microglobulin, we identify the interactions that inhibit or promote fibril formation in atomic detail. The results reveal that different outcomes of assembly result from biomolecular interactions involving similar surfaces. Specifically, inhibition occurs via rigid body docking of monomers in a head-to-head orientation to form kinetically trapped dimers. By contrast, the promotion of fibrillation involves relatively weak protein association in a similar orientation, which results in conformational changes in the initially nonfibrillogenic partner. The results highlight the complexity of interactions early in amyloid assembly and reveal atomic-level information about species barriers in amyloid formation.
    Molecular Cell 06/2014; 55(2). DOI:10.1016/j.molcel.2014.05.026 · 14.46 Impact Factor
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    • "A number of factors have been identified that alter the kinetics of amyloid fibril formation in solution: lowered pH, increased temperature and agitation as well as increased concentration of amyloid have all been shown to accelerate amyloid aggregation (Harper & Lansbury, 1997; Buell et al., 2012; Crespo et al., 2012). It has also been shown that the toxicity of amyloid species is highly dependent on the structural flexibility and exposure of hydrophobic residues of the peptide (Campioni et al., 2010). "
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    ABSTRACT: Abstract Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by dementia and memory loss for which no cure or effective prevention is currently available. Neurodegeneration in AD is linked to formation of amyloid plaques found in brain tissues of Alzheimer's patients during post-mortem examination. Amyloid plaques are composed of amyloid fibrils and small oligomers - insoluble protein aggregates. Although amyloid plaques are found on the neuronal cell surfaces, the mechanism of amyloid toxicity is still not well understood. Currently, it is believed that the cytotoxicity is a result of the nonspecific interaction of small soluble amyloid oligomers (rather than longer fibrils) with the plasma membrane. In recent years, nanotechnology has contributed significantly to understanding the structure and function of lipid membranes and to the study of the molecular mechanisms of membrane-associated diseases. We review the current state of research, including applications of the latest nanotechnology approaches, on the interaction of lipid membranes with the amyloid-β (Aβ) peptide in relation to amyloid toxicity. We discuss the interactions of Aβ with model lipid membranes with a focus to demonstrate that composition, charge and phase of the lipid membrane, as well as lipid domains and rafts, affect the binding of Aβ to the membrane and contribute to toxicity. Understanding the role of the lipid membrane in AD at the nanoscale and molecular level will contribute to the understanding of the molecular mechanism of amyloid toxicity and may aid into the development of novel preventive strategies to combat AD.
    Drug Metabolism Reviews 02/2014; DOI:10.3109/03602532.2014.882354 · 6.29 Impact Factor
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    • "We show, in addition, that this uptake is rapid and spontaneous, that it occurs without any apparent accumulation of peptide molecules in the plasma membrane, that it is temperature-dependent, and that the internalized peptide molecules colocalize with markers for endocytosis and acidic vesicular organelles. Taken together, these observations indicate that monomeric Ab(1–40) and Ab(1–42) are both taken up into the cells as monomers and via active endocytotic pathways, although it has been shown that other amyloid species, including oligomers (Campioni et al., 2010) and fibrils (Kaminski Schierle et al., 2011b; McGuire et al., 2012), if present in the cellular medium, can also be taken up via nonendocytotic pathways. We observe retention of Ab in acidic compartments over 48 hr, suggesting their localization in lysosomes in accord with the findings of several previous studies (Burdick et al., 1997; Hu et al., 2009; Knauer et al., 1992). "
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