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J. Biol. Chem., Vol. 278, Issue 44, 43717-43727, October 31, 2003
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¶**
From the
Laboratories of Structural Biology, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, and Biochemistry and Genetics, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 and the ||Department of Biology, Brookhaven National Laboratories, Upton, New York 11973
The [URE3] prion is an inactive, self-propagating, filamentous form of the Ure2 protein, a regulator of nitrogen catabolism in yeast. The N-terminal "prion" domain of Ure2p determines its in vivo prion properties and in vitro amyloid-forming ability. Here we determined the overall structures of Ure2p filaments and related polymers of the prion domain fused to other globular proteins. Protease digestion of 25-nm diameter Ure2p filaments trimmed them to 4-nm filaments, which mass spectrometry showed to be composed of prion domain fragments, primarily residues 
1–70. Fusion protein filaments with diameters of 14–25 nm were also reduced to 4-nm filaments by proteolysis. The prion domain transforms from the most to the least protease-sensitive part upon filament formation in each case, implying that it undergoes a conformational change. Intact filaments imaged by cryo-electron microscopy or after vanadate staining by scanning transmission electron microscopy (STEM) revealed a central 4-nm core with attached globular appendages. STEM mass per unit length measurements of unstained filaments yielded 1 monomer per 0.45 nm in each case. These observations strongly support a unifying model whereby subunits in Ure2p filaments, as well as in fusion protein filaments, are connected by interactions between their prion domains, which form a 4-nm amyloid filament backbone, surrounded by the corresponding C-terminal moieties.
Received for publication, June 6, 2003 , and in revised form, August 6, 2003.
* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains Figs. S1 and S2 and Table SI.
¶ Present address: Nabi Biopharmaceuticals, Rockville, MD 20852.
** To whom correspondence should be addressed: Bldg. 50, Rm. 1517, 50 South Dr., MSC 8025, Bethesda, MD 20892-8025. Tel.: 301-496-0132; Fax: 301-480-1191; E-mail: Alasdair_Steven{at}nih.gov.
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