. Interaction of intracellular beta amyloid peptide with chaperone proteins. Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9439-44. PubMed.

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  1. Fonte et al. study an intracellular aggregation of Aβ in the transgenic C. elegance model they developed. Fonte et al. identify proteins that interact with Ab in vivo. The authors find six likely chaperone proteins (HSP70, HSP16 families, and a putative
    ortholog of a mammalian small glutamine-rich tetratricopeptide (SGT), believed to regulate HSP70) that coimmunoprecipitate with Aβ42.
    To examine the specificity of the Aβ42 interaction with chaperone proteins, the authors developed a nonamyloidic Aβ variant --- the single-chain Aβ dimer. The authors discover that despite the high level of expression of the dimer, transgenicC. elegance do not produce detectable amyloid deposits and show significantly reduced levels of paralysis. Interestingly, the pattern of expressed HSPs is significantly different: HSP70 and HSP16 are absent or drastically reduced. The results strongly suggest that the chaperone response is very specific to conformational or toxic properties of Aβ and is not a general response to high expression of a foreign protein. The work of Fonte et al. also suggests that toxic precursor amyloids of Aβ42 have specific three-dimensional structural organization.

    From molecular dynamics simulations of another protein, Src SH3 domain, we have recently observed two types of dimeric forms of Src SH3 --- closed and open dimers (Ding et al. submitted). The closed dimeric form is formed by a domain-swapping mechanism (Bennett, MJ et al) and is not prone to further aggregation upon addition of multiple SH3 domains. In contrast, the open dimeric form was shown to further aggregate as we added more SH3 domains to our simulations. Thus, there may be a parallel between the work of Fonte et al. and ours --- it is possible that a single-chain Aβdimer is analogous to our closed form of SH3 dimer, incapable of further aggregation, while an open form SH3 dimer is analogous to monomeric Aβ42. Such a parallel suggests the importance of the conformational specificity of amyloid Aβ42 aggregates.-- Nikolay V. Dokholyan, Harvard University, Department of Chemistry and Chemical Biology, 12 Oxford Street, Cambridge MA 02138

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