The mechanism of prion inhibition by HET-S

Mol Cell. 2010 Jun 25;38(6):889-99. doi: 10.1016/j.molcel.2010.05.019.


HET-S (97% identical to HET-s) has an N-terminal globular domain that exerts a prion-inhibitory effect in cis on its own prion-forming domain (PFD) and in trans on HET-s prion propagation. We show that HET-S fails to form fibrils in vitro and that it inhibits HET-s PFD fibrillization in trans. In vivo analyses indicate that beta-structuring of the HET-S PFD is required for HET-S activity. The crystal structures of the globular domains of HET-s and HET-S are highly similar, comprising a helical fold, while NMR-based characterizations revealed no differences in the conformations of the PFDs. We conclude that prion inhibition is not encoded by structure but rather in stability and oligomerization properties: when HET-S forms a prion seed or is incorporated into a HET-s fibril via its PFD, the beta-structuring in this domain induces a change in its globular domain, generating a molecular species that is incompetent for fibril growth.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Fungal Proteins / chemistry*
  • Fungal Proteins / genetics
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Prions / chemistry*
  • Prions / genetics
  • Protein Conformation
  • Protein Multimerization
  • Protein Stability
  • Protein Structure, Tertiary
  • Solutions


  • Fungal Proteins
  • HET-S protein, Podospora anserina
  • Prions
  • Solutions