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A more recent version of this article appeared on May 1, 2004
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Submitted on August 14, 2002
Revised on February 2, 2004
Accepted on February 3, 2004
1 Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois, 60637; Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
2 Committee on Genetics, The University of Chicago, Chicago, Illinois, 60637
3 Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois, 60637
4 Department of Molecular Genetics and Cell Biology, Committee on Genetics, The University of Chicago, Chicago, Illinois, 60637, Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142
* Corresponding author. E-mail address: lindquist admin{at}wi.mit.edu.
Heat-shock protein 104 (Hsp104p) is a protein-remodeling factor that promotes survival after extreme stress by disassembling aggregated proteins and can either promote or prevent the propagation of prions (protein-based genetic elements). Hsp104p can be greatly overexpressed without slowing growth, suggesting tight control of its powerful protein remodeling activities. We isolated point mutations in Hsp104p that interfere with this control and block cell growth. Each mutant contained alterations in the middle region (MR). Each of the three MR point mutations analyzed in detail had distinct phenotypes. In combination with nucleotide binding-site mutations, Hsp104pT499I altered bud morphology and caused septin mislocalization, colocalizing with the misplaced septins. Point mutations in the septin Cdc12p suppressed this phenotype, suggesting that it is due to direct Hsp104p-septin interactions. Hsp104pA503V did not perturb morphology but stopped cell growth. Remarkably, when expressed transiently, the mutant protein promoted survival after extreme stress as effectively as did wild-type Hsp104p. Hsp104pA509D had no deleterious effects on growth or morphology but had a greatly reduced ability to promote thermotolerance. That mutations in an 11 amino-acid stretch of the MR have such profound and diverse effects suggests the MR plays a central role in regulating Hsp104p function.
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