A protein constructed de novo enables cell growth by altering gene regulation

Katherine M. Digianantonio, Michael H. Hecht

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Recent advances in protein design rely on rational and computational approaches to create novel sequences that fold and function. In contrast, natural systems selected functional proteins without any design a priori. In an attempt to mimic nature, we used large libraries of novel sequences and selected for functional proteins that rescue Escherichia coli cells in which a conditionally essential gene has been deleted. In this way, the de novo protein SynSerB3 was selected as a rescuer of cells in which serB, which encodes phosphoserine phosphatase, an enzyme essential for serine biosynthesis, was deleted. However, SynSerB3 does not rescue the deleted activity by catalyzing hydrolysis of phosphoserine. Instead, SynSerB3 upregulates hisB, a gene encoding histidinol phosphate phosphatase. This endogenous E. coli phosphatase has promiscuous activity that, when overexpressed, compensates for the deletion of phosphoserine phosphatase. Thus, the de novo protein SynSerB3 rescues the deletion of serB by altering the natural regulation of the His operon.

Original languageEnglish (US)
Pages (from-to)2400-2405
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number9
StatePublished - Mar 1 2016

All Science Journal Classification (ASJC) codes

  • General


  • Auxotroph
  • De novo protein design
  • HisB
  • SerB
  • Synthetic biology


Dive into the research topics of 'A protein constructed de novo enables cell growth by altering gene regulation'. Together they form a unique fingerprint.

Cite this