De novo design of synthetic prion domains

Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6519-24. doi: 10.1073/pnas.1119366109. Epub 2012 Apr 2.


Prions are important disease agents and epigenetic regulatory elements. Prion formation involves the structural conversion of proteins from a soluble form into an insoluble amyloid form. In many cases, this structural conversion is driven by a glutamine/asparagine (Q/N)-rich prion-forming domain. However, our understanding of the sequence requirements for prion formation and propagation by Q/N-rich domains has been insufficient for accurate prion propensity prediction or prion domain design. By focusing exclusively on amino acid composition, we have developed a prion aggregation prediction algorithm (PAPA), specifically designed to predict prion propensity of Q/N-rich proteins. Here, we show not only that this algorithm is far more effective than traditional amyloid prediction algorithms at predicting prion propensity of Q/N-rich proteins, but remarkably, also that PAPA is capable of rationally designing protein domains that function as prions in vivo.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Amino Acid Sequence
  • Molecular Sequence Data
  • Prions / chemistry*
  • Sequence Homology, Amino Acid
  • Solubility


  • Prions