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    Trigger factor slows co-translational folding through kinetic trapping while sterically protecting the nascent chain from aberrant Cytosolic interactions

    O’Brien, E.P. and Christodoulou, John and Vendruscolo, M. and Dobson, C.M. (2012) Trigger factor slows co-translational folding through kinetic trapping while sterically protecting the nascent chain from aberrant Cytosolic interactions. Journal of the American Chemical Society 134 (26), pp. 10920-10932. ISSN 0002-7863.

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    Abstract

    In conformational diseases, native protein conformers convert to pathological intermediates that polymerize. Structural characterization of these key intermediates is challenging. They are unstable and minimally populated in dynamic equilibria that may be perturbed by many analytical techniques. We have characterized a forme fruste deficiency variant of α1-antitrypsin (Lys154Asn) that forms polymers recapitulating the conformer-specific neo-epitope observed in polymers that form in vivo. Lys154Asn α1-antitrypsin populates an intermediate ensemble along the polymerization pathway at physiological temperatures. Nuclear magnetic resonance spectroscopy was used to report the structural and dynamic changes associated with this. Our data highlight an interaction network likely to regulate conformational change and do not support the recent contention that the disease-relevant intermediate is substantially unfolded. Conformational disease intermediates may best be defined using powerful but minimally perturbing techniques, mild disease mutants, and physiological conditions.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 20 May 2013 12:03
    Last Modified: 06 Dec 2016 10:48
    URI: http://eprints.bbk.ac.uk/id/eprint/6889

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