Journal
MOLECULAR CELL
Volume 38, Issue 6, Pages 889-899Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2010.05.019
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Funding
- Schweizerische Nationalfonds (SNF)
- National Institutes of Health (NIH)
- Agence Nationale de la Recherche (ANR)
- Department of Energy (DOE), Office of Biological and Environmental Research
- NIH, National Center for Research Resources
- National Institute of General Medical Sciences
- DOE, Office of Basic Energy Sciences [DE-AC02-05CH11231]
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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.
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