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The mechanism of prion inhibition by HET-S.

ABSTRACT: 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.

SUBMITTER: Greenwald J

PROVIDER: S-EPMC3507513 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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The mechanism of prion inhibition by HET-S.

Greenwald Jason J Buhtz Carolin C Ritter Christiane C Kwiatkowski Witek W Choe Senyon S Maddelein Marie-Lise ML Ness Frederique F Cescau Sandra S Soragni Alice A Leitz Dominik D Saupe Sven J SJ Riek Roland R

Molecular cell 20100601 6

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 f ...[more]

PMID: 20620958

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