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    Systematic mapping of free energy landscapes of a growing filamin domain during biosynthesis

    Waudby, C.A. and Wlodarski, T. and Karyadi, M.-E. and Cassaignau, A.M.E. and Chan, S.H.S. and Wentink, A.S. and Schmidt-Engler, J.M. and Camilloni, C. and Vendruscolo, M. and Cabrita, L.D. and Christodoulou, John (2018) Systematic mapping of free energy landscapes of a growing filamin domain during biosynthesis. Proceedings of the National Academy of Sciences of the United States of America 115 (39), pp. 9744-9749. ISSN 0027-8424.

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    Abstract

    Cotranslational folding (CTF) is a fundamental molecular process that ensures efficient protein biosynthesis and minimizes the formation of misfolded states. However, the complexity of this process makes it extremely challenging to obtain structural characterizations of CTF pathways. Here, we correlate observations of translationally arrested nascent chains with those of a systematic C-terminal truncation strategy. We create a detailed description of chain length-dependent free energy landscapes associated with folding of the FLN5 filamin domain, in isolation and on the ribosome, and thus, quantify a substantial destabilization of the native structure on the ribosome. We identify and characterize two folding intermediates formed in isolation, including a partially folded intermediate associated with the isomerization of a conserved cis proline residue. The slow folding associated with this process raises the prospect that neighboring unfolded domains might accumulate and misfold during biosynthesis. We develop a simple model to quantify the risk of misfolding in this situation and show that catalysis of folding by peptidyl-prolyl isomerases is sufficient to eliminate this hazard. [Abstract copyright: Copyright © 2018 the Author(s). Published by PNAS.]

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): cotranslational folding, molecular dynamics simulations, nuclear magnetic resonance, protein misfolding, tandem repeat protein
    School: School of Science > Biological Sciences
    SWORD Depositor: Mr Joe Tenant
    Depositing User: Mr Joe Tenant
    Date Deposited: 01 Oct 2018 08:50
    Last Modified: 09 Feb 2021 21:29
    URI: https://eprints.bbk.ac.uk/id/eprint/24032

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