A Protein Chimera Strategy Supports Production of a Model “Difficult-to-Express” Recombinant Target

Hirra Hussain, Manuel Carballo Amador, Robert A. Roth, Alan Dickson, David Fisher, William Abbott, James Warwicker

    Research output: Contribution to journalArticlepeer-review


    Due in part to the needs of the biopharmaceutical industry, there has been an increased drive to generate high quality recombinant proteins in large amounts. However, achieving high yields can be a challenge as the novelty and increased complexity of new targets often makes them ‘difficult-to-express’. This study aimed to define the molecular features that restrict the production of a model ‘difficult-to-express’ recombinant protein, Tissue Inhibitor Metalloproteinase-3 (TIMP-3). Building from experimental data, computational approaches were used to rationalize the redesign of this recombinant target to generate a chimera with enhanced secretion. The results highlight the importance of early identification of unfavourable sequence attributes, enabling the generation of engineered protein forms that bypass ‘secretory’ bottlenecks and result in efficient recombinant protein production.

    Original languageEnglish
    Pages (from-to)2499-2511
    Number of pages13
    JournalFEBS Letters
    Issue number14
    Early online date30 Jul 2018
    Publication statusPublished - 30 Jul 2018


    • difficult-to-express
    • mammalian expression system
    • predictive computational tool
    • protein engineering
    • recombinant protein production
    • tissue inhibitor of metalloproteinase


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