Translational tuning optimizes nascent protein folding in cells

Soo Jung Kim, Jae Seok Yoon, Hideki Shishido, Zhongying Yang, LeeAnn A. Rooney, Jose M. Barral, William R. Skach

    Research output: Contribution to journalArticlepeer-review

    105 Scopus citations

    Abstract

    In cells, biosynthetic machinery coordinates protein synthesis and folding to optimize efficiency and minimize off-pathway outcomes. However, it has been difficult to delineate experimentally the mechanisms responsible. Using fluorescence resonance energy transfer, we studied cotranslational folding of the first nucleotide-binding domain from the cystic fibrosis transmembrane conductance regulator. During synthesis, folding occurred discretely via sequential compaction of N-terminal, α-helical, and α/β-core subdomains. Moreover, the timing of these events was critical; premature α-subdomain folding prevented subsequent core formation. This process was facilitated by modulating intrinsic folding propensity in three distinct ways: delaying a-subdomain compaction, facilitating β-strand intercalation, and optimizing translation kinetics via codon usage. Thus, de novo folding is translationally tuned by an integrated cellular response that shapes the cotranslational folding landscape at critical stages of synthesis.

    Original languageEnglish (US)
    Pages (from-to)444-448
    Number of pages5
    JournalScience
    Volume348
    Issue number6233
    DOIs
    StatePublished - Apr 24 2015

    ASJC Scopus subject areas

    • General

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