Nov 8, 2018

Consensus sequence design as a general strategy to create hyperstable, biologically active proteins

BioRxiv : the Preprint Server for Biology
Matt SternkeDoug Barrick


Consensus sequence design offers a promising strategy for designing proteins of high stability while retaining biological activity since it draws upon an evolutionary history in which residues important for both stability and function are likely to be conserved. Although there have been several reports of successful consensus design of individual targets, it is unclear from these anecdotal studies how often this approach succeeds, and how often it fails. Here, we attempt to assess generality by designing consensus sequences for a set of six protein families with a range of chain-lengths, structures, and activities. We characterize the resulting consensus proteins for stability, structure, and biological activities in an unbiased way. We find that all six consensus proteins adopt cooperatively folded structures in solution. Strikingly, four out of six of these consensus proteins show increased thermodynamic stability over naturally-occurring homologues. Each consensus protein tested for function maintained at least partial biological activity. Though peptide binding affinity by a consensus-designed SH3 is rather low, Km values for consensus enzymes are similar to values from extant homologues. Though consensus enzymes are slower...Continue Reading

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Mentioned in this Paper

Conserved Sequence
Enzymes, antithrombotic
Cell Polarity
Enzymes for Treatment of Wounds and Ulcers
Binding (Molecular Function)
Biochemical Turnover

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