The Mechanism of Prion Inhibition by HET-S

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 vi...

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Published in:Molecular cell 2010-06, Vol.38 (6), p.889-899
Main Authors: Greenwald, Jason, Buhtz, Carolin, Ritter, Christiane, Kwiatkowski, Witek, Choe, Senyon, Maddelein, Marie-Lise, Ness, Frederique, Cescau, Sandra, Soragni, Alice, Leitz, Dominik, Saupe, Sven J., Riek, Roland
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Biochemistry
Biochemistry, Molecular Biology
Bioengineering
Cancer
Cellular Biology
Crystallography, X-Ray
Fungal Proteins - chemistry
Fungal Proteins - genetics
Life Sciences
Models, Molecular
Molecular biology
Molecular Sequence Data
Mutation
Neurobiology
Neurons and Cognition
Pharmaceutical sciences
Prions - chemistry
Prions - genetics
Protein Conformation
Protein Multimerization
Protein Stability
Protein Structure, Tertiary
PROTEINS
Solutions
Structural Biology
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Summary: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 β-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 β-structuring in this domain induces a change in its globular domain, generating a molecular species that is incompetent for fibril growth. ► HET-S inhibits its own fibril formation as well as that of HET-s ► The structures of the N-terminal domains of HET-S and HET-s are very similar ► The prion inhibition mechanism relies on the stability of the N-terminal domain
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2010.05.019