5 years ago

A pH Switch for β-Sheet Protein Folding

A pH Switch for β-Sheet Protein Folding
Niels H. Andersen, Jordan M. Anderson
Protein design advancements have led to biotechnological strategies based on more stable and more specific structures. Herein we present a 6-residue sequence (HPATGK) that acts as a stable structure-nucleating turn at physiological and higher pH but is notably unfavorable for chain direction reversal at low pH. When placed into the turn of a β-sheet, this leads to a pH switch of folding. Using a standard 3-stranded β-sheet model, the WW domain, it was found that the pH switch sequence insertion caused minimal change at pH 8 but a ca. 50 °C drop in the melting temperature (Tm) was observed at pH 2.5: ΔΔGF ≥11.3 kJ mol−1. Using the strategies demonstrated in this article, the redesign of β-sheets to contain a global, or local, pH-dependent conformational switch should be possible. Designer protein: With biotechnology looking for more ways to control the conformation of proteins, a simple mutation to create a pH switchable β-sheet is presented. Using a six-residue sequence in the turn-nucleating hairpin of a β-sheet, global folding can be controlled. With the sheet being fully folded at physiologic pH and unfolded at pH 2.5.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201700860

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