The Mechanism of Prion Inhibition by HET-S

被引：62

作者：

Greenwald, Jason ^{[1
]}

Buhtz, Carolin ^{[1
]}

Ritter, Christiane ^{[2
]}

Kwiatkowski, Witek ^{[3
]}

Choe, Senyon ^{[3
]}

Maddelein, Marie-Lise ^{[4
]}

Ness, Frederique ^{[4
]}

Cescau, Sandra ^{[4
]}

Soragni, Alice ^{[1
]}

Leitz, Dominik ^{[1
]}

Saupe, Sven J. ^{[4
]}

Riek, Roland ^{[1
,3
]}

机构：

[1] Swiss Fed Inst Technol, Phys Chem Lab, CH-8093 Zurich, Switzerland

[2] Helmholtz Ctr Infect Res, D-38124 Braunschweig, Germany

[3] Salk Inst Biol Studies, Struct Biol Lab, La Jolla, CA 92037 USA

[4] Univ Bordeaux 2, Lab Genet Mol Champignons, Inst Biochim & Genet Cellulaires, CNRS,UMR 5095, F-33077 Bordeaux, France

来源：

MOLECULAR CELL | 2010年 / 38卷 / 06期

基金：

美国国家卫生研究院;

关键词：

FUNGUS PODOSPORA-ANSERINA; VEGETATIVE INCOMPATIBILITY; HETEROKARYON INCOMPATIBILITY; IN-VIVO; PROTEIN; AGGREGATION; DOMAIN; YEAST; REGION; CORE;

D O I：

10.1016/j.molcel.2010.05.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：889 / 899

页数：11

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