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    A Systematic study of the effect of physiological factors on beta2-microglobulin amyloid formation at neutral pH

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    Publication date
    2006
    Author
    Jones, Susan
    Myers, S.L.
    Radford, S.E.
    Tennent, G.A.
    Keyword
    (beta(2)m) forms amyloid fibrils
    Fibril-seeds
    Beta(2)m fibrillogenesis
    DeltaN6
    Fibril formation
    Fibril extension
    Fibrillogenesis
    Peer-Reviewed
    Yes
    
    Metadata
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    Abstract
    ß2-microglobulin (ß2m) forms amyloid fibrils that deposit in the musculo-skeletal system in patients undergoing long-term hemodialysis. How ß2m self-assembles in vivo is not understood, since the monomeric wild-type protein is incapable of forming fibrils in isolation in vitro at neutral pH, while elongation of fibril-seeds made from recombinant protein has only been achieved at low pH or at neutral pH in the presence of detergents or cosolvents. Here we describe a systematic study of the effect of 11 physiologically relevant factors on ß2m fibrillogenesis at pH 7.0 without denaturants. By comparing the results obtained for the wild-type protein with those of two variants (¿N6 and V37A), the role of protein stability in fibrillogenesis is explored. We show that ¿N6 forms low yields of amyloid-like fibrils at pH 7.0 in the absence of seeds, suggesting that this species could initiate fibrillogenesis in vivo. By contrast, high yields of amyloid-like fibrils are observed for all proteins when assembly is seeded with fibril-seeds formed from recombinant protein at pH 2.5 stabilized by the addition of heparin, serum amyloid P component (SAP), apolipoprotein E (apoE), uremic serum, or synovial fluid. The results suggest that the conditions within the synovium facilitate fibrillogenesis of ß2m and show that different physiological factors may act synergistically to promote fibril formation. By comparing the behavior of wild-type ß2m with that of ¿N6 and V37A, we show that the physiologically relevant factors enhance fibrillogenesis by stabilizing fibril-seeds, thereby allowing fibril extension by rare assembly competent species formed by local unfolding of native monomers.
    URI
    http://hdl.handle.net/10454/2693
    Version
    No full-text available in the repository
    Citation
    Jones, Susan., Myers, S.L., Radford, S.E. et al. (2006). A Systematic study of the effect of physiological factors on beta2-microglobulin amyloid formation at neutral pH. Biochemistry. Vol.45, No. 7, pp.2311-2321.
    Link to publisher’s version
    http://pubs.acs.org/doi/full/10.1021/bi052434i
    Type
    Article
    Collections
    Life Sciences Publications

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