Engineered domain swapping as an on/off switch for protein function

Jeung Hoi Ha, Joshua M. Karchin, Nancy Walker-Kopp, Carlos A. Castañeda, Stewart N. Loh

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Domain swapping occurs when identical proteins exchange segments in reciprocal fashion. Natural swapping mechanisms remain poorly understood, and engineered swapping has the potential for creating self-assembling biomaterials that encode for emergent functions. We demonstrate that induced swapping can be used to regulate the function of a target protein. Swapping is triggered by inserting a "lever" protein (ubiquitin) into one of four loops of the ribose binding protein (RBP) target. The lever splits the target, forcing RBP to refold in trans to generate swapped oligomers. Identical RBP-ubiquitin fusions form homo-swapped complexes with the ubiquitin domain acting as the hinge. Surprisingly, some pairs of non-identical fusions swap more efficiently with each other than they do with themselves. Nuclear magnetic resonance experiments reveal that the hinge of these hetero-swapped complexes maps to a region of RBP distant from both ubiquitins. This design is expected to be applicable to other proteins to convert them into functional switches.

Original languageEnglish (US)
Pages (from-to)1384-1393
Number of pages10
JournalChemistry and Biology
Issue number10
StatePublished - Oct 22 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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